USPTO Patents Application 09993647

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date
31 October 2002 (31.10.2002)

PCT

(10) International Publication Number

WO 02/085859 Al

(51) International Patent Classification 7 : C07D 213/75,

217/22, 401/12, 215/38, 403/12, A61K 31/44, 31/47,
A61P 29/00

65 Winterhill Road, Madison, CT 06443 (US). WOOD,
Jill, E. [US/US]; 3007 Ridge Road, North Haven, CT
06473 (US).

(21) International Application Number: PCT/US02/12064

(22) International Filing Date: 17 April 2002 (17.04.2002)

(25) Filing Language:

(26) Publication Language:

(30) Priority Data:

09/838,286

English

English

20 April 2001 (20.04.2001) US

(71) Applicant (for all designated States except US): BAYER
CORPORATION [US/US]; 100 Bayer Road, Pittsburgh,
PS 15205 (US).

(72) Inventors; and

(75) Inventors/Applicants (for US only): DUMAS, Jacques

[FR/US] ; 98 Farmview Road, Bethany, CT 06524 (US).
RIEDL, Bernd [DE/DE]; Von der Goltz Strasse 7, 42329
Wuppertal (DE). KHIRE, Uday [EN/US] ; 101 Tanglewood
Drive, Hamden, CT 06518 (US). SIBLEY, Robert, N.
[US/US]; 1187 Mt. Carmel Avenue, North Haven, CT
06473 (US). HATOUM-MOKDAD, Holia [US/US]; 43
Joseph Lane, Hamden, CT 06514 (US). MONAHAN,
Mary-Katherine [US/US]; 134 Park Avenue, Hamden,
CT 06517 (US). GUNN, David, E. [US/US]; 40 Wood
Street, Hamden, CT 06517 (US). LOWINGER, Timothy,
B. [CA/JP]; Wotanstrasse 11, D-42117 Wuppertal (DE).
SCOTT, William, J. [US/US]; 210 Saddle Hill Drive,
Guilford, CT 06437 (US). SMITH, Roger, A. [US/US];

(74) Agents: ZELANO, Anthony, J. et al.; Millen, White, Ze-
lano & Branigan, P.C., Suite 1400, Arlington Courthouse
Plaza I, 2200 Clarendon Boulevard, Arlington, VA 22201
(US).

(81) Designated States (national): AE, AG, AL, AM, AT, AU,

AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
MX, MZ, NO, NZ, PH, PL, PT, RO, RU, SD, SE, SG, SI,
SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU,
ZA, ZW.

(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR,
GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OAPI patent
(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
NE, SN, TD, TG).

Published:

— with international search report

— before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
amendments

For two-letter codes and other abbreviations, refer to ihe "Guid-
ance Notes on Codes and Abbreviations " appearing at the begin-
ning of each regular issue of the PCT Gazette-

9\

oo

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(54) Title: HETEROARYL UREAS CONTAINING NITROGEN HETERO-ATOMS AS p38 KINASE INHIBITORS

(57) Abstract: This invention relates to the use of a group of heteroaryl ureas containing nitrogen in treating p38 mediated diseases,
and pharmaceutical compositions for use in such therapy.

WO 02/085859

PCT/US02/12064

HETEROARYL UREAS CONTAINING NITROGEN HETERO-ATOMS AS

p38 KINASE INHIBITORS

Cross Reference to Related Applications

This is a continuation-in-part of application Serial No. 09/778,039 filed February
7, 2001, which is a continuation-in-part of Serial No. 09/425,229 filed October 22, 1999,
which is a continuation of 09/257,265 filed February 25, 1999 which claims priority to
provisional application 60/115,878, filed January 13, 1999.

Field of the Invention

This invention relates to the use of a group of heteroaryl ureas containing nitrogen
hetero atoms in treating cytokine mediated diseases and proteolytic enzyme' mediated
25 diseases, and pharmaceutical compositions for use in such therapy.

Background of the Invention

Two classes of effector molecules which are critical for the progression of
rheumatoid arthritis are pro-inflammatory cytokines and tissue degrading proteases.
30 Recently, a family of kinases was described which is instrumental in controlling the
transcription and translation of the structural genes coding for these effector molecules.

The mitogen-activated protein (MAP) kinase family is made up of a series of
structurally related proline-directed serine/threonine kinases which are activated either by
growth factors (such as EGF) and phorbol esters (ERIC), or by JJL-1, TNFa or stress (p38,
35 JNK). The MAP kinases are responsible for the activation of a wide variety of

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transcription factors and proteins involved in transcriptional control of cytokine
production. A pair of novel protein kinases involved in the regulation of cytokine
synthesis was recently described by a group from SmithKline Beecham (Lee et al. Nature
1994, 372, 739). These enzymes were isolated based on their affinity to bond to a class
5 of compounds, named CSAEDSs (cytokine suppressive anti-inflammatory drugs) by
SKB. The CSAIDs, bicyclic pyridinyl imidazoles, have been shown to have cytokine
inhibitory activity both in vitro and in vivo. The isolated enzymes, CSBP-1 and -2
(CSATD binding protein 1 and 2) have been cloned and expressed. A murine homologue
for CSBP-2, p38, has also been reported (Han et al. Science 1994, 265, 808).

10 Early studies suggested that CSAIDs function by interfering with m-RNA

translational events during cytokine biosynthesis. Inhibition of p38 has been shown to
inhibit both cytokine production (eg., TNFa, IL-1, IL-6, EL-8) and proteolytic enzyme
production (eg., MMP-1, MMP-3) in vitro and/or in vivo.

Clinical studies have linked TNFa production and/or signaling to a number of

15 diseases including rheumatoid arthritis (Maini. J. Royal Coll. Physicians London 1996,
30, 344). In addition, excessive levels of TNFa have been implicated in a wide variety
of inflammatory and/or immunomodulatory diseases, including acute rheumatic fever
(Yegin et al. Lancet 1997, 349, 170), bone resorption (Pacifici et al. J. Clin. Endocrinol.
Metabol. 1991, 82, 29), postmenopausal osteoperosis (Pacifici et al. /. Bone Mineral Res.

20 1996, 11, 1043), sepsis (Blackwell et al. Br. J. Anaesth. 1996, 77, 110), gram negative
sepsis (Debets et al. Prog. Clin. Biol. Res. 1989, 308, 463), septic shock (Tracey et al.
Nature 1987, 330, 662; Girardin et al. New England J. Med. 1988, 319, 397), endotoxic
shock (Beutler et al. Science 1985, 229, 869; Ashkenasi et al. Proc. Nat 'I. Acad. Sci. USA
1991, 88, 10535), toxic shock syndrome, (Saha et al. J. Immunol. 1996, 157, 3869; Lina

25 et al. FEMS Immunol. Med. Microbiol. 1996, 13, 81), systemic inflammatory response
syndrome (Anon. Crit. Care Med. 1992, 20, 864), inflammatory bowel diseases
(Stokkers et al. J. Inflamm. 1995-6, 47, 97) including Crohn's disease (van Deventer et
al. Aliment. Pharmacol. Therapeu. 1996, 10 (Suppl. 2), 107; van Dullemen et al.
Gastroenterology 1995, 109, 129) and ulcerative colitis (Masuda et al. J. Clin. Lab.

30 Immunol. 1995, 46, 111), Jarisch-Herxheimer reactions (Fekade et al. New England J.
Med. 1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13, 539), adult

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respiratory distress syndrome (Roten et al. Am. Rev. Respir. Dis. 1991, 143, 590; Suter et
al. Am. Rev. Respir. Dis. 1992, 145, 1016), acute pulmonary fibrotic diseases (Pan et al.
Pathol. Int. 1996, 46, 91), pulmonary sarcoidosis (Ishioka et al. Sarcoidosis Vasculitis
Diffuse Lung Dis. 1996, 13, 139), allergic respiratory diseases (Casale et al. Am. J.
5 Respir. Cell Mol. Biol. 1996, 15, 35),- silicosis (Gossart et al. J. Immunol. 1996, 156,
1540; Vanhee et al. Eur. Respir. J. 1995, 8, 834), coal worker's pneumoconiosis (Borm
et al. Am. Rev. Respir. Dis. 1988, 138, 1589), alveolar injury (Horinouchi et al. Am. J.
Respir. Cell Mol. Biol. 1996, 14, 1044), hepatic failure (Gantner et al. J. Pharmacol. Exp.
Therap. 1997, 280, 53), liver disease during acute inflammation (Kim et al. J. Biol.

10 Chem. 1997, 272, 1402), severe alcoholic hepatitis (Bird et al. Ann. Intern. Med. 1990,
112, 917), malaria (Grau et al. Immunol. Rev. 1989, 112, 49; Taveme et al. Parasitol.
Today 1996, 12, 290) including Plasmodium falciparum malaria (Perlmann et al. Infect.
Immunit. 1997, 65, 116) and cerebral malaria (Rudin et al. Am. J. Pathol. 1997, 150,
257), non-insulin-dependent diabetes mellitus (NIDDM; Stephens et al. J. Biol. Chem.

15 1997, 272, 971; Ofei et al. Diabetes 1996, 45, 881), congestive heart failure (Doyama et
al. Int. J. Cardiol. 1996, 54, 217; McMurray et al. Br. Heart J. 1991, 66, 356), damage
following heart disease (Malkiel et al. Mol. Med. Today 1996, 2, 336), atherosclerosis
(Parums et al. J. Pathol. 1996, 179, A46), Alzheimer's disease (Fagarasan et al. Brain
Res. 1996, 723, 231; Aisen et al. Gerontology 1997, 43, 143), acute encephalitis

20 (Ichiyama et al. J. Neurol. 1996, 243, 457), brain injury (Cannon et al. Crit. Care Med.
1992, 20, 1414; Hansbrough et al. Surg. Clin. N. Am. 1987, 67, 69; Marano et al. Surg.
Gynecol. Obstetr. 1990, 170, 32), multiple sclerosis (M.S.; Coyle. Adv. Neuroimmunol.
1996, 6, 143; Matusevicius et al. J. Neuroimmunol. 1996, 66, 115) including demyelation
and oligiodendrocyte loss in multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6,

25 243), advanced cancer (MucWierzgon et al. J. Biol. Regulators Homeostatic Agents
1996, 10, 25), lymphoid malignancies (Levy et al. Crit. Rev. Immunol. 1996, 16, 31),
pancreatitis (Exley et al. Gut 1992, 33, 1126) including systemic complications in acute
pancreatitis (McKay et al. Br. J. Surg. 1996, 83, 919), impaired wound healing in
infection inflammation and cancer (Buck et al. Am. J. Pathol. 1996, 149, 195),

30 myelodysplastic syndromes (Raza et al. Int. J. Hematol. 1996, 63, 265), systemic lupus
erythematosus (Maury et-al. Arthritis Rheum. 1989, 32, 146), biliary cirrhosis (Miller et

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al. Am. J. Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al. J. Clin. Invest.

1988, 81, 1328), psoriasis (Christophers. Austr. J. Dermatol. 1996, 37, S4), radiation
injury (Redlich et al. J. Immunol 1996, 157, 1705), and toxicity following administration
of monoclonal antibodies such as OKT3 (Brod et al. Neurology 1996, 46, 1633). TNFa

5 levels have also been related to host-versus-graft reactions (Piguet et al. Immunol. Ser.
1992, 56, 409) including ischemia reperfusion injury (Colletti et al. Clin. Invest. 1989,
85, 1333) and allograft rejections including those of the kidney (Maury et al. J. Exp.
Med. 1987, 166, 1132), liver (hnagawa et al. Transplantation 1990, 50, 219), heart
(Boiling et al. Transplantation 1992, 53, 283), and skin (Stevens et al. Transplant. Proc.
10 1990, 22, 1924), lung allograft rejection (Grossman et al. Immunol. Allergy Clin. N. Am.

1989, 9, 153) including chronic lung allograft rejection (obliterative bronchitis; LoCicero
et al. J. Thorac. Cardiovasc. Surg. 1990, 99, 1059), as well as complications due to total
hip replacement (Cirino et al. Life Sci. 1996, 59, 86). TNFa has also been linked to
infectious diseases (review: Beutler et al, Crit. Care Med. 1993, 21, 5423; Degre.

15 Bio therapy 1996, 8, 219) including tuberculosis (Rook et al. Med. Malad. Infect. 1996,
26, 904), Helicobacter pylori infection during peptic ulcer disease (Beales et al.
Gastroenterology 1997, 112, 136), Chaga's disease resulting from Trypanosoma cruzi
infection (Chandrasekar et al. Biochem. Biophys. Res. Commun. 1996, 223, 365), effects
of Shiga-like toxin resulting from E. coli infection (Harel et al. J. Clin. Invest. 1992, 56,

20 ' 40), the effects of enterotoxin A resulting from Staphylococcus infection (Fischer et al. J.
Immunol. 1990, 144, 4663), meningococcal infection (Waage et al. Lancet 1987, 355;
Ossege et al. J. Neurolog. Set 1996, 144, 1), and infections from Borrelia burgdorferi
(Brandt et al. Infect. Immunol 1990, 58, 983), Treponema pallidum (Chamberlin et al.
Infect. Immunol. 1989, 57, 2872), cytomegalovirus (CMV; Geist et al. Am. J. Respir. Cell

25 Mol Biol. 1997, 16, 31), influenza virus (Beutler et al. Clin. Res. 1986, 34, 491a), Sendai
virus (Goldfield et al. Proc. Nat 'I. Acad. Sci. USA 1989, 87, 1490), Theiler's
encephalomyelitis virus (Sierra et al. Immunology 1993, 78, 399), and the human
immunodeficiency virus (HIV; Poli. Proc. Nat 'I. Acad. Sci. USA 1990, 87, 782;
Vyakaram et al. AIDS 1990, 4, 21; Badley et al. J. Exp. Med. 1997, 185, 55).

30 Because inhibition of p38 leads to inhibition of TNFa production, p38 inhibitors

will be useful in treatment of the above listed diseases.

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A number of diseases are thought to be mediated by excess or undesired matrix-
destroying metalloprotease (MMP) activity or by an imbalance in the ratio of the MMPs
to the tissue inhibitors of metalloproteinases (TIMPs). These include osteoarthritis
(Woessner et al. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis (Mullins et al.
5 Biochim. Biophys. Acta 1983, 695, 117; Woolley et al. Arthritis Rheum. 1977, 20, 1231;
Gravallese et al. Arthritis Rheum. 1991, 34, 1076), septic arthritis (Williams et al.
Arthritis Rheum. 1990, 33, 533), tumor metastasis (Reich et al. Cancer Res. 1988, 48,
. 3307; Matrisian et al. Proc. Nat'l. Acad. Set, USA 1986, 83, 9413), periodontal diseases
(Overall et al. J. Periodontal Res. 1987, 22, 81), corneal ulceration (Bums et al. Invest.

10 Opthalmol Vis. Sci. 1989, 30, 1569), proteinuria (Baricos et al. Biochem. J. 1988, 254,
609), coronary thrombosis from atherosclerotic plaque rupture (Henney et al. Proc. Nat'l.
Acad. Set, USA 1991, 88, 8154), aneurysmal aortic disease (Vine et al. Clin. Sci. 1991,
81, 233), birth control (Woessner et al. Steroids 1989, 54, 491), dystrophobic
epidermolysis bullosa (Kronberger et al. J. Invest. Dermatol. 1982, 79, 208),

15 degenerative cartilage loss following traumatic joint injury, osteopenias mediated by
MMP activity, tempero mandibular joint disease, and demyelating diseases of the
nervous system (Chantry et al. J. Neurochem. 1988, 50, 688).

Because inhibition of p38 leads to inhibition of MMP production, p38 inhibitors
will be useful in treatment of the above listed diseases.

20 Inhibitors of p38 are active in animal models of TNFa production, including a

muirne lipopolysaccharide (LPS) model of TNFa production. Inhibitors of p38 are
active in a number of standard animal models of inflammatory diseases, including
carrageenan-induced edema in the rat paw, arachadonic acid-induced edema in the rat
paw, arachadonic acid-induced peritonitis in the mouse, fetal rat long bone resorption,

25 murine type II collagen-induced arthritis, and Fruend's adjuvant-induced arthritis in the
rat. Thus, inhibitors of p38 will be useful in treating diseases mediated by one or more of
the above-mentioned cytokines and/or proteolytic enzymes.

The need for new therapies is especially important in the case of arthritic
diseases. The primary disabling effect of osteoarthritis, rheumatoid . arthritis and septic

30 arthritis is the progressive loss of articular cartilage and thereby normal joint function.
No marketed pharmaceutical agent is able to prevent or slow this cartilage loss, although

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nonsteroidal antiinflammatory drugs (NSAIDs) have been given to control pain and
swelling. The end result of these diseases is total loss of joint function which is only
treatable by joint replacement surgery. P38 inhibitors will halt or reverse the progression
. of cartilage loss and obviate or delay surgical intervention.
5 Several patents have appeared claiming polyarylimidazoles and/or compounds

containing polyarylimidazoles as inhibitors of p38 (for example, Lee et al. WO 95/07922;
Adams et al. WO 95/02591; Adams et al. WO 95/13067; Adams et al. WO 95/31451). It
has been reported that arylimidazoles complex to the ferric form of cytochrome P450 cam
(Harris et al. Mol Eng. 1995, 5, 143, and references therein), causing concern that these
10 compounds may display structure-related toxicity (Howard-Martin et al. Toxicol. Pathol.
1987, 15, 369). Therefore, there remains a need for improved p38 inhibitors.

Summary of the Invention

This invention provides compoimds, generally described as heteroaryl ureas

15 containing nitrogen hetero atoms, including pyridine, quinoline and isoquinoline. ureas,
which inhibit p38 mediated events and thus inhibit the production of cytokines (such as
TNFa, IL-1 and IL-8) and proteolytic enzymes (such as MMP-1 and MMP-3). The
invention also provides compositions which contain heteroaryl ureas and a method of
treating a cytokine mediated disease state in humans or mammals with heteroaryl ureas,

20 wherein the cytokine is one whose production is affected by p38. Examples of such
cytokines include, but are not limited to TNFa, EL-l and EL-8. The invention also
provides a method of treating a protease mediated disease state, in.humans or mammals,
wherein the protease is one whose production is affected by p38, e.g. disease states
mediated by one or more cytokines or proteolytic enzymes produced and/or activated by

25 a p38 mediated process. Examples of such proteases include, but are not limited to
collagenase (MMP-1) and stromelysin (MMP-3).

Accordingly, these compounds are useful therapeutic agents for such acute and
chronic inflammatory and/or immunomodulatory diseases as rheumatoid arthritis,
osteoarthritis, septic arthritis, rheumatic fever, bone resorption, postmenopausal

30 osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock
syndrome, systemic inflammatory response syndrome, inflammatory bowel diseases

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including Crohn's disease and ulcerative colitis, Jarisch-Herxheimer reactions, asthma,
adult respiratory distress syndrome, acute pulmonary fibrotic diseases, pulmonary
sarcoidosis, allergic respiratory diseases, silicosis, coal worker's pneumoconiosis,
alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic
5 hepatitis, malaria including Plasmodium falciparum malaria and cerebral malaria, non-
insulin-dependent diabetes mellitus (NTJDDM), congestive heart failure, damage
following heart disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain
injury, multiple sclerosis including demyelation and oligodendrocyte loss in multiple
sclerosis, advanced cancer, lymphoid malignancies, tumor metastasis, pancreatitis,

10 including systemic complications in acute pancreatitis, impaired wound healing in
infection, inflammation and cancer, periodontal diseases, corneal ulceration, proteinuria,
myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel
necrosis, psoriasis, radiation injury, toxicity following administration of monoclonal
antibodies such as OKT3, host-versus-graft reactions including ischemia reperfusion

15 . injury and allograft rejections including kidney, liver, heart, and skin allograft rejections,
lung allograft rejection including chronic lung allograft rejection (obliterative bronchitis)
as well as complications due to total hip replacement, and infectious diseases including
tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's disease
resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin resulting from E.

20 coli infection, effects of enterotoxin A resulting from Staphylococcus infection,
meningococcal infection, and infections from Borrelia burgdorferi, Treponema pallidum,
cytomegalovirus, influenza virus, Theiler's encephalomyelitis, virus, and the human
immunodeficiency virus (HIV).

The present invention, therefore, provides hetaryl urea compounds containing

25 nitrogen hetero-atoms, and compositions which comprise hetaryl urea compounds
containing nitrogen heteroatoms and a method for treating of p38-mediated disease states
in humans or mammals, e.g., disease states mediated by one or more cytokines or
proteolytic enzymes produced and/or activated by a p38 mediated process. In these
methods a compound of formula I, or a pharmaceutically acceptable salt thereof, is

30 administered,

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A-D-B (I).

In formula I,

D is -NH-C(0)-NH-,

A is a substituted or unsubstituted pyridyl, quinolinyl or isoquinoliyl group,

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up
to 50 carbon atoms with a cyclic structure bound directly to D containing at least 5
members with 0-4 members of the group consisting of nitrogen, oxygen and sulfur.

The moiety B is preferably either a substituted or unsubstituted bridged cyclic
structure of up to 30 carbon atoms of the formula -L-(ML') q , a substituted or
unsubstituted 6 member cyclic aryl moiety or hetaryl moiety or a substituted or
unsubstituted 2-3 fused ring structure (aryl, hetaryl or both). For Example, B can be
phenyl, substituted phenyl, napthyl substituted napthyl, pyridinyl, substituted pyridinyl,
pyrirnidinyl, substituted pyrimidinyl, quinolinyl, substituted quinolinyl, isoqxiinolinyl,
substituted isoquinolinyl or of the formula -L(ML l ) q .

L in the formula -L(ML') q is a 5 or 6 membered cyclic structure bond directly to
D, L 1 is a cyclic moiety of at least 5 members,

M is a bridging group having at least one atom and q is an integer of 1-3.

Each cyclic structure of L and L 1 contains from 0-4 members of the group
consisting of N, O and S.

The substituents for the groups of A are preferably selected from the group
consisting of halogen, up to per-halo, and Wn, where n is 0-3 and each W is
independently selected from the group consisting of Ci-io alkyl, Cho alkoxy, C3.10
cycloalkyl having at least five cyclic members and 0-3 heteroatoms, C2-10 alkenyl, C1-10
alkenoyl, substituted Cmo alkyl, substituted Ci-10 alkoxy, a substituted C3,io cycloalkyl
having at least 5 cyclic members and 0-3 heteroatoms selected from N, S and O;
substituted C2-10 alkenyl, substituted Q. 10 alkenoyl, C6-C14 aryl, C7-C24 alkaryl, C7 -C24

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aralkyl, C3-C12 hetaryl having at least 5 cyclic members and 1-3 heteroatoms selected
from O, N and S, C4-C23 alkheteroaryl having at least 5 cyclic members and 1-3
heteroatoms selected from O, N and S, substituted Q-C14 aryl, substituted C3-C12 hetaryl
having at least 5 members and 1-3 heteroatoms selected from O, N and S, substituted C 7 -
C 2 4 aralkyl, substituted C7-C24 alkaryl, substituted C4-C23 alkheteroaryl having at least 5
cyclic members and 1-3 heteroatoms selected from O, N and S; -CN, -C0 2 R 7 , -
C(0)NR 7 R 7 ', -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 ', -NR 7 C(0)OR 7 ', -NR 7 C(0)R 7 ', with
each R 7 and R 7 independently selected from hydrogen, Cmo alkyl, Cmo alkoxy, C 2 -io
alkenyl, Ci- 10 alkenoyl, up to per halosubstituted C M0 alkyl, up to per halosubstituted Ci-
10 allcoxy, up to per halosubstituted C2-10 alkenyl and up to per halosubstituted C1-10
alkenoyl, C3-C10 cycloalkyl having at least 5 cyclic members and 0-3 heteroatoms
selected from O, S and N, C6-C14 aryl, C3-C10 hetaryl having at least 5 cyclic members
and 0-3 heteroatoms selected from O, S and N, up to per halosubstituted C3-C10
cycloalkyl having at least 6 cyclic members and 0-3 heteroatoms selected from O, S and
N, up to per halo substituted C6-C14 aryl, and. up to per halo substituted C3-C10 hetaryl
having at least 6 cyclic members and 0-3 heteroatoms selected from O, S and N.

Where W is a substituted group, it is substituted by halogen, up to per halo, or by
one or more substituents independently selected from the group consiting of -CN,
-C0 2 R 7 , -C(0)NR 7 R 7 ", -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 ', -NR 7 C(0)OR 7 ', -
NR 7 C(0)R 7 with each R 7 and R 7 independently as defined above.

Where B, is substituted, the substituents are selected from the group consisting of
halogen, up to per-halo, and J n , where n is 0-3'ahd"eacH J is independently selected from
the group consisting of -CN, -C0 2 R 7 , -C(0)NR 7 R 7 ', -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -
NR 7 R 7 ', -NR 7 C(0)OR 7 ', -NR 7 C(0)R 7 ', with each R 7 and R 7 ' independently as defined
above , Cmo alkyl, Cmo alkoxy, C3.10 cycloalkyl having at least five cyclic members and
0-3 heteroatoms, C2-10 alkenyl, Cmo alkenoyl,- C 6 -i4 aryl, C3.12 hetaryl having at least five
cyclic members and 1-3 heteroatoms selected from N, S and O, C 7 - 24 aralkyl, C7-24
alkaryl, C4-C 2 3 alkheteroaryl having at least 5 cyclic members and 1-3 heteroatoms
selected from O, N and S, substituted Cmo alkyl, substituted Cmo alkoxy, substituted C 3 _
10 cycloalkyl having at least five cyclic members and 0-3 heteroatoms selected from N, S
and O, substituted C2-10 alkenyl substituted C M o alkenoyl, substituted -Cu aryl,

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substituted C3-12 hetaryl having at least five cyclic members and 1-3 hetero atoms selected
from N, S and O, substituted C7-24 alkaryl , substituted C7-C24 aralkyl substituted C4-C23
alkheteroaryl having at least 5 cyclic members and 1-3 heteroatoms selected from O, N
and S, and -Q-Ar.

Where J is a substituted group, it is substituted by halogen, up to per halo, or by .
one or more substituents independently selected from the group consisting of -CN, -
CO2R 7 , -C(0)-R 7 , -C(0)NR 7 R 7 ', -OR 7 , -SR 7 , -NR 7 R 7 ', -N0 2 , -NR 7 C(0)R 7 ', and -
NR 7 C(0)OR 7 ' ; with each R 7 and R 7 independently as defined above for W.

Where J is -Q-Ar, Q is preferably a single bond, -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -
C(O)-, -CH(OH)-, -(CH 2 ) m O-, -(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - ,-CHX a -, -CX a 2 -, -
S-(CH2) m - and -N(R 7 )(CH 2 ) m -, where m= 1-3, and X a is halogen and

Ar is a 5- or 6-member aromatic structure. This aromatic structure of Ar

a) contains 0-2 members selected from the group consisting of nitrogen, oxygen
and sulfur,

b) is optionally substituted by halogen, up to per-halo, and

c) is optionally substituted by Z nl , wherein nl is 0 to 3 and each Z is
independently selected from the group consisting of -CN, -N0 2 , -OR 7 , - SR 7 ,
-NR 7 R 7 ', -NR 7 C(0)0R 7 ', -NR 7 C(0)R 7 ', with each R 7 and R 7 ' independently
as defined above for W, Gi.io-alkyL : C1.10 alkoxy, C 2 .io alkenyl and Cmo
alkenoyl halo substituted Ci-io alkyl up to per halo, halo substituted Cmo
alkoxy up to per halo, halosubstituted C2-10 alkenyl up to per halo and
halosubstituted C1.10 alkenoyl up to per halo.

Where A is a substituted pyridyl, substituted quinolinyl or isoquinolinyl group, A
is preferably substituted 1 to 3 times by 1 or more substituents selected from the group
consisting of — CN, halogen, Q-C10 alkyl, C1-C10 alkoxy, -OH, up to per halo substituted
C1-C10 alkyl, up to per halo substituted C1-C10 alkoxy or phenyl substituted by halogen up
to per halo.

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Where B is -L^ML 1 ^, L 1 can be substituted by the substituents -C(0)R a , -
C(NR a )R b , -C(0)NR a R b , -S0 2 NR a R b , -and -S0 2 R a wherein each R a and R b are
independently hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally
containing heteroatoms selected from N, S and O, and optionally substituted by halogen.

5 R a and R b preferably are each, independently, Cmo alkyl, Cmo alkoxy, C 3 .i 0

cycloalkyl having at least 5 cyclic members and 0-3 heteroatoms selected from N, S and
O, C2-10 alkenyl, Cwo alkenoyl, Ce-i4 aryl, C3-12 hetaryl having 1-3 heteroatoms selected
from N, S and O, C7.24 aralkyl, C7.24 alkaryl, substituted Cmo alkyl, substituted Cmo
alkoxy, substituted C3-10 cycloalkyl having at least 5 cyclic members and 0-3 heteroatoms

10 selected from N, S and O, substituted C2-10 alkenyl, substituted Cmo alkenoyl, substituted
C6 -C14 aryl, substituted C3-12 hetaryl having at least 5 ' cyclic members and 1-3
heteroatoms selected from N, S and O, substituted C7.24 alkaryl or substituted C7-C24
aralkyl. Where R a and/or R b are a substituted group, they are substituted by halogen up
to per halo hydroxy, Cmo alkyl, C3.12 cycloalkyl having 0-3 heteroatoms selected from O,

15 S and N, C3.12 hetaryl having 1-3 heteroatoms selected from N, S and O, Cmo alkoxy, C6-
12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to
per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected fromN,
S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo
heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24

20 alkaryl up to per halo alkaryl, and -C(0)R g .

R a and R b can also be

-OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24
carbon atoms optionally containing heteroatoms selected from N, S and O and optionally
substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms,
25 which optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen; or

b) 'bound together to form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic
structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy

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or carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen; or

c) one of R a or R b can be -C(O)-, a C1-C5 divalent alkylene group or a
substituted C1-C5 divalent alkylene group bound to the moiety L to form a cyclic
5 structure with at least 5 members, wherein the substituents of the substituted C1-C5

divalent alkylene group are selected from the group consisting of halogen, hydroxy, and
carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen.

The carbon based moieties of R f and the substituents on R a and R b include C1-10
10 'alkyl, Ci-10 alkyl, Clio alkoxy, C3-C10 cycloalkyl having 0-3 heteroatoms selected from
O, S and N, Ce-i2 aryl, C3-C12 hetaryl having 1-3 heteroatoms selected from O, S and N,
C7-24 aralkyl, substituted Clio alkyl, substituted C1-C10 alkoxy, substituted C3-Ci2-
cycloalkyl having 0-3 heteroatoms selected from O, S and N, substituted C3-C12 heteraryl
having 1-3 heteroatoms selected from O, S, and N, substituted C5.12 aryl, and substituted
15 C7.24 alkaryl, where Rf is a substituted group it is substituted halogen up to per halo,

hydroxy, Clio alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N,
C3-12 hetaryl having 1-3 heteroatoms selected fromN, S and O, Ci-io alkoxy, Cg-u aryl,
C y .-C24 alkaryl, C7-C24 aralkyl, Ci-6 halo substituted alkyl up to per halo alkyl, C6-C12
halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3
20 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12
hetaryl up to per halo heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl,
halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(0)R g ;

where R g is Clio alkyl; -CN, -C0 2 Rd, -ORd, -SRd, -N0 2 , -C(O) Re, -NRaRe, -NR d
C(0)ORe and -NRj C(0)Re, and Rd and Re are independently selected from the group
25 consisting of hydrogen, Cuo, alkyl, Clio alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms
selected from O, N and S, C6-12 aryl, C3-C12 hetaryl with 1-3 heteroatoms selected from
O, N and S and C7-C24 aralkyl, C7-C24 alkaryl, up to per halo substituted C1-C10 alkyl, up
to per halo substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and
S, up to per halo substituted C6-C14 aryl, up to per halo substituted C3-C12 hetaryl having

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1-3 heteroatoms selected from O, N, and S, halo substituted C7-C 24 allcaryl up to per halo
alkaryl, and up to per halo substituted C7-C24 aralkyl.

The bridging group M in the formula -^(ML 1 ),, for B is preferably selected from
the group consisting of-O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(0>, -CH(OH)-, -(CH 2 ) m O,
-( CH 2 ) ra S-, -( CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX\ -CXV, -S-(CH 2 ) m -, -N(R 7 )(CH 2 ) m - and
-CR a R b - where m=l-3, X a is hydrogen, R 7 , R a and R b are as defined above and q is 1.
More preferably, M is -0-, -CH 2 -, -S-, -NH-, -C(O)-, -0-CH 2 - and -CH3-O-.

The moieties L and L 1 in the formula — L-(ML 1 ) q for B are typically each,
independently, a substituted aryl moiety having at least 6 cyclic members, a substituted
heterocyclic moiety having at least 5 cyclic members, an unsubstituted aryl moiety
having at least 6 cyclic members or an unsubstituted heterocyclic moiety having at least 5
cyclic members. The heterocyclic and hetaryl moietes for L and L' typically have 1 to 4
members selected from the group of hetero atoms consisting of nitrogen, oxygen and
sulfur with the balance of the hetaryl or heterocyclic moiety being carbon. More typical
moieties for L 1 and L are selected from the group consisting of tbiophene, substituted
thiophene, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl and
substituted pyrimidinyl.

Where L is substituted or L 1 is additionally substituted, the substituents are
selected from the group consisting of halogen, up to per-halo, and Jn where n is 0-3, and J
is as defined above.

Preferred compounds of Formula I include those wherein the cyclic structures of
B and L bound directly to D are not substituted in the ortho position by-OH.

The invention provides hetaryl compounds containing nitrogen hetero-atoms of
formula II

A'-D-B'OI),

wherein D is as defined above for formula I and A' is either a substituted t-
butylpyridyl, unsubstituted t-butylpyridyl, substituted (trifluoromethyl)pyridyl,
unsubstituted (trifluoromethyl)pyridyl, substituted isopropylpyridyl, unsubstituted
sopropylpyridyl, substituted " (2-methylr2-butyl)pyridyl, unsubstituted (2-mefhyl-2-

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butyl)pyridyl, substituted (3-ethyl-3-pentyl)pyridyl, unsubstituted (3-ethyl-3-
pentyl)pyridyl, substituted isoquinolinyl, unsubstituted isoquinolinyl or unsubstituted
quinolinyl.

B' can be a substituted or unsubstituted 6 member cyclic aryl ring, at least a 5
member heterocylic ring or from 2-3 fused rings of up to 30 carbon atoms (aryl hetaryl or
both).

B' also includes structures of formula EH

either substituted or unsubstituted, where A' is substituted or \insubstituted t-butylyridyl,
(trifluoromethyl)pyridyl, isopropylpyridyl, (2-methyl-2-butyl)pyridyl or (3-ethyl-3-
pentyl)pyridyl.

B' also includes structures of the formula IV

either substituted or unsubstituted where A' is a substituted isoquinolinyl, unsubsituted
isoquinolinyl or unsubstituted quinolinyl group.

The substituents for the substituted groups of A' are as defined for A. Preferred
substituents are selected from the group consisting of up to per halo substituted C]_io
alkoxy, up to per halo substituted Cmo alkyl and C3.10 heteroyclic moieties comprising 1
to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

(Ill)

N

(IV)

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Where B' is a 6 member cyclic arylring, at least a 5 member heterocyclic ring or
2-3 fused rings of up to 30 carbon atoms, the substituents for B' are selected from the
group consisting of halogen, up to per-halo-, and J 1 !, where n=0-3 and each J 1 is
independently selected from the group consisting of -CN, halogen, OH, -C0 2 R 7 ,-
5 C(0)NR 7 R 7 ', -C(0)-R 7 , N0 2 , OR 7 , SR 7 , NR 7 R 7 ', NR 7 C(0)OR 7 ', NR 7 C(0)R 7 ', Ci.i Q alkyi,
Ci-io alkoxy, C2-10 alkenyl, Ci-10 alkenoyl, substituted Ci-10 alkyl, substituted Ci.iq alkoxy,
substituted C2-10 alkenyl, and substituted Cmo alkenoyl, with R 7 and R 7 are,
independently, as defined above.

When B' is of formula EH or IV, the substituents are selected from the group

10 consisting of-CN, halogen, OH, -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 ', -NR 7 C(0)OR 7 ', C M0 alkyl,
Ci-10 alkoxy, C 2 -io alkenyl, Ci-io alkenoyl, substituted Ci-10 alkoxy, substituted • C2-10
alkenyl and substituted alkenoyl Ci-10, withR 7 andR 7 as defined above.

R a and R b preferably are each, independently, Ci-10 alkyi, Ci-io alkoxy,' C3-10
cycloalkyl having at least 5 cyclic members and 0-3 heteroatoms, C2-10 alkenyl, Ci-io

15 alkenoyl, C6-12 aryl, C3.12 hetaryl having at least 5 cyclic members and 1-3 heteroatoms
selected from N, S and O, C7J24 aralkyl, C7-24 alkaryl, substituted Ci_i 0 alkyl, ' substituted
Ci-io alkoxy, substituted C3.10 cycloalkyl having at least 5 cyclic members and 0-3
heteroatoms selected from N, S and O, substituted C2-10 alkenyl, substituted Ci-10
alkenoyl, substituted Ce -Cu aryl, substituted C3-12 hetaryl having at least 5 cyclic

20 members and 1-3 heteroatoms selected from N, S and O, substituted C7-24 alkaryl or
substituted C 7 -C 2 4 aralkyl, where R a and/or R b are a substituted group, they are preferably
substituted by halogen up to per halo.

Where B 5 is' a substituted pyridyl, substituted quinolinyl or isoquinolihyl group,
B' is preferably substituted 1 to 3 times by 1 or more substituents selected from the group
25 consisting of -CN, halogen, C1-C10 alkyl, C1-C10 alkoxy, -OH, up to per halo substituted
C1-C10 alkyl, up to per halo substituted C1-C10 alkoxy or phenyl substituted by halogen up
to per halo.

In Formulae I, and II suitable hetaryl groups include, but are not limited to, 4-12
30 carbon- atom aromatic rings or ring systems containing 1-3 rings, at least one of which is
aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be

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replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 5-7 member atoms.
For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl,
1-, 2-, 4- or 5-irnidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-
isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-
pyrimidinyl, 1,2,3-triazol-l-, -4- or-5-yl, 1,2,4-triazol-l-, -3- or-5-yl, 1- or 5-tetrazolyl,

1.2.3- oxadiazol-4- or-5-yl, l,2,4-oxadiazol-3- or-5-yl, l,3,4-thiadiazol-2- or-5-yl,

1.2.4- oxadiazol-3- or-5-yl, l,3,4-thiadiazol-2- or-5-yl, l,3,4-tbiadiazol-3- or-5-yl,
l,2,3-thiadiazol-4- or-5-yl, 2-, 3- 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl,

3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-
benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-
, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl,
1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-
benz-l,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7~ or 8-quinolinyl, 1-, 3-, 4-, 5- 6-, 7-, 8-
isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-,

4- , 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-'
thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For
example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, l-methyl-3-
pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-l,2,4-thiadiazol-2-yl.

Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout
include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched
isomers such -as, isopropyl, isobutyl, sec-butyl, rert-butyl, etc.

Suitable aryl groups which do not contain heteroatoms include, for example,
phenyl and 1 - and 2-naphthyl.

The term "cycloalkyl", as used herein, refers to cyclic structures with or without
alkyl substituents such that, for example, "C 4 cycloalkyl" includes methyl substituted
cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl", as used herein
also includes saturated heterocyclic groups.

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Suitable halogen groups include F, CI, Br, and/or I, from one to per-substitution
(i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl
group is substituted by halogen, mixed substitution of halogen atom types also being
possible on a given moiety.

5

The present invention is also directed to pharmaceutically acceptable salts of
formula H Suitable pharmaceutically acceptable salts are well known to those skilled in
the art and include basic salts of inorganic and organic acids, such as hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid,

10 trifluoromethanesulfonic acid, benzenesulphonic acid^-toluenesulfonic acid, 1-

naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid,
malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid,
maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid, in
addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as

15 salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 ,
Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including
aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such
as those arising from protonation or peralkylation of triethylamine, N,N-dieihylamme,
A^iV"-dicyclohexylamme, lysine, pyridine, MTV-dimethylaminopyridine (DMAP), 1,4-

20 diazabiclo[2.2.2]octane'(DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU).

A number of the compounds of Formulae I and 1 1 possess asymmetric carbons and can
therefore exist in racemic and optically active forms. Methods of separation of
25 enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The
present invention encompasses any racemic or optically active form of compounds
described in Formula II which possess progesterone receptor binding activity.

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General Preparative Methods

The compounds of Formulae I and II may be prepared by the use of known chemical
reactions and procedures, some from starting materials which are commercially available.
5 Nevertheless, general preparative methods are provided below to aid one skilled in the art
in synthesizing these compounds, with more detailed examples being provided in the
Experimental section which follows.

Substituted and unsubstituted aminoquinolines, aminoisoquinolines and aminopyridines
may be prepared using standard methods (see, for example: A.R. Katritzky et al. (Eds.).
10 Comprehensive Heterocyclic Chemistry II, Vol. 5. M.H. Palmer. Heterocyclic

Compounds; Arnold Ltd., London (1967). C.K. Esser et al. WO 96/18616. C.J. Donahue
et al. Inorg. Chem. 30, 1991, 1588. E. Cho et al. WO 98/00402. A. Cordi et al. Bioorg.
Med. Chem.. 3, 1995, 129). In addition, many aminoquinolines, aminoisoquinolines and
aminopyridines are commercially available.

15

Substituted anilines may be generated using standard methods (March. Advanced
Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock. Comprehensive
Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I,
aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst,

20 ' such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene,
or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK
(1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as
LiAlH.4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic
Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe,

25 Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls

(March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock.
Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

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H 2 / catalyst -
^ (eg. Ni, Pd, Pt) \^

ArN0 2 ^ >► ArNH 2

\ M(0)

(eg. Fe, Sn, Ca)
Scheme I Reduction of Nitroaryls to Aryl Amines

Nitroaryis are commonly formed by electrophilic aromatic nitration using HNO3, or an
alternative N02 + source. Nitroaryls may be further elaborated prior to reduction. Thus,
nitroaryls sxibstituted with

HNO3

Ar-H >- ArN0 2

potential leaving groups (eg. F, CI, Br, etc.) may undergo substitution reactions on
treatment with nucleophiles, such as thiolate (exemplified in Scheme H) or phenoxide.
Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).

Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls
Nitroaryls may also undergo transition metal mediated cross coupling reactions. For
example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo
palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic
acids (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs
(Negishi reaction) to afford the biaryl (5).

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0 2 N

ArB(OR') 2

0 2 N

Ar

R

Pd(0)

R

4

5

Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl
chloride (7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with
a fluoride source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl

as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the
corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be
reduced to the arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with
CHC1F 2 in the presence of base gives the difluoromethyl mercaptan (11), which maybe
oxidized to the sulfone (12) with any of a variety of oxidants, including Cr03-acetic
anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568).

fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such

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Scheme HI Selected Methods of Fluorinated Aryl Sulfone Synthesis
As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an
ary] isocyanate (14) with an aryl amine (13). The heteroary'l isocyanate may be
5 synthesized from a heteroaryl amine by treatment with phosgene or a phosgene
equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl)
carbonate (triphosgene), or A^A^'-carbonyldiimidazole (GDI). The isocyanate may also
be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide
or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16
10 with an azide source, followed by rearrangement affords the isocyanate. The
corresponding carboxylic acid (17) may also be subjected to Curtius-type rearrangements
using diphenylphosphoryl azide (DPP A) or a similar reagent.

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Ar 1 — NH 2 13

COCl 2

, ' H 2 N— Ar 2
Ar n -NCO >>

ArV.,A.„

14

N N
H H

15

Ar

DP PA

O

.,A.

O

Ar' X Ar' OH

16 17

Scheme IV Selected Methods of Non-Symmetrical Urea Formation

Finally, ureas may be further manipulated using methods familiar to those skilled in the
art.

The invention also includes pharmaceutical compositions including a compound of
Formula I, and a physiologically acceptable carrier.

The compounds may be administered orally, dermally, parenterally, by injection, by
inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations. The
term 'administration by injection' includes intravenous, intraarticular, intramuscular,
subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal
administration may include topical application or transdermal administration. One or
more compotmds may be present in association with one or more non-toxic
pharmaceutically acceptable carriers and if desired other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method
known to the art for the manufacture of pharmaceutical compositions. Such
compositions may contain one or more agents selected from the group consisting of
diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in
order to provide palatable preparations. Tablets contain the active ingredient in

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admixture with non-toxic pharmaceutically acceptable excipients which are suitable for
the manufacture of tablets. These excipients may be, for example, inert diluents, such as
calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or alginic acid; and
5 binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated by known techniques to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a sustained action over a
longer period. For example, a time delay material such as glyceryl monostearate or
glyceryl distearate may be employed. These compounds may also be prepared in solid,
10 rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the
active ingredient is mixed with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is
15 mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions containing the active materials in admixture with excipients
suitable for the manufacture of aqueous suspensions may also be used. Such excipients
are suspending agents, for example sodium carboxymethylcellulose, methylcellulose,

20 hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth
and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide,
for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for
example polyoxyethylene stearate, or condensation products of ethylene oxide with long
chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation

25 products of ethylene oxide with partial esters derived from fatty acids and hexitol such as
polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with
partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one or more
preservatives, for example ethyl, or rc-propyl,/?-hydroxybenzoate, one or more coloring

30 agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose
or saccharin.

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Dispersible powders and granules suitable for preparation of an aqueous suspension by
the addition of water provide the active ingredient in admixture with a dispersing or
wetting agent, suspending agent and one or more preservatives. Suitable dispersing or
wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example, sweetening, flavoring and coloring agents, may also
be present.

The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily
suspensions which may be formulated by suspending the active ingredients in a vegetable
oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening agent, for example
beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above,
and flavoring agents may be added to provide palatable oral preparations. These
compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water
emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a
mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents
may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-
occurring phosphatides, for example soy bean, lecithin, and esters or partial esters
derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and
condensation products of the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a
preservative and flavoring and coloring agents.

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The compounds may also be administered in the form of suppositories for rectal or
vaginal administration of the drug. These compositions can be prepared by mixing the
drug with a suitable non-irritating excipient which is solid at ordinary temperatures but
liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina
5 to release the drug. Such materials include cocoa butter and polyethylene glycols.

Compounds of the invention may also be administered transdermally using methods
known to those skilled in the art (see, for example: Chien; "Transdermal Controlled •
Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. WO94/04157 3Mar94).

10 For example, a solution or suspension of a compound of Formula I in a suitable volatile
solvent optionally containing penetration enhancing agents can be combined with
additional additives known to those skilled in the art, such as matrix materials and
bacteriocides. After sterilization, the resulting mixture can be formulated following
known procedures into dosage forms. In addition, on treatment with emulsifying agents

15 and water, a solution or suspension of a compound of Formula I maybe formulated into a
lotion or salve.

Suitable solvents for processing transdermal delivery systems are known to those skilled
in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones

20 such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as
tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or
halogenated hydrocarbons such as dichlorometbane, chloroform, trichlorotrifluoroethane,
or trichlorofluoroethane. Suitable solvents may also include mixtures one or more
materials selected from lower alcohols, lower ketones , lower carboxylic acid esters,

25 polar ethers, lower hydrocarbons, halogenated hydrocarbons.

Suitable penetration enhancing materials for transdermal delivery systems are known to
those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols
such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated Cg-Cis fatty
30 alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaftirated Cs-Ci8 fatty

acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such

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as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tert-butyl or monoglycerin
esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic
acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24
carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl
5 maleate, or diisopropyl fumarate. Additional penetration enhancing materials include

phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and
their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl
ether. Suitable penetration enhancing formulations may also include mixtures one or
more materials selected from monohydroxy or polyhydroxy alcohols, saturated or
10 unsaturated Cs-Cis fatty alcohols, saturated or unsaturated Cs-Cis fatty acids, saturated or
unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated
dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes,
amides, ketones, ureas and their derivatives, and ethers.

15 Suitable binding materials for transdermal delivery systems are known to those skilled in
the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-
butadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized
polyethylenes, and silicates may also be used as matrix components. Additional
additives, such as viscous resins or oils maybe added to increase the viscosity of the

20 matrix.

For all regimens of use disclosed±atemJbr compounds of Formulae I and II, the daily
oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The
daily dosage for administration by injection, including intravenous, intramuscular,

25 subcutaneous and parenteral injections, and use of infusion techniques will preferably be
from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will
preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage
regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. These daily
dosages can be administered incrementally during the day, on a weekly basis on a

30 biweekly basis or longer periods. Long term dosages typically range from 100-600

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mg/kg of total body weight-arid preferably range from 100-400 mg/kg of total body
weight.

Dosages for oral, vaginal and rectal administration and administration by injection
can range from 0.01 mg — 600 mg/kg of total body weight.

5

The daily topical dosage regimen will preferably be from 0. 1 to 200 mg
administered between one to four times daily. The transdermal concentration will
preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The
daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body
10 weight.

It will be appreciated by those skilled in the art that the particular method of
administration will depend on a variety of factors, all of which are considered routinely
when administering therapeutics. It will also be understood, however, that the specific

15 dose level for any given patient will depend upon a variety of factors, including, but not
limited to the activity of the specific compound employed, the age of the patient, the
body weight of the patient, the general health of the patient, the gender of the patient, the
diet of the patient, time of administration, route of administration, rate of excretion, drug
combinations, and the severity of the condition undergoing therapy. It will be further

20 appreciated by one skilled in the art that the optimal course of treatment, ie., the mode Of
treatment and the daily or weekly number of doses of a compound of Formulae I or H or
a pharmaceutically acceptable salt+hereof given, for a defined.number of days, can be
ascertained by those skilled in the art using conventional treatment tests.

25 The entire disclosure of all applications, patents and publications cited above and below
are hereby incorporated by reference, including provisional application Serial No.
60/115,878 filed January 13, 1999 and non-provisional applications
Serial No. 09/778,039, filed February 7, 2001, and
Serial No. 09/257,265, filed February 25, 1999 and
30 Serial No. 09/425,229, filed October 22, 1999.

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The compounds of formulae I and II are producible from known compounds (or from
starting materials which, in turn, are producible from known compounds), e.g., through
the general preparative methods shown below. ' The activity of a given compound to
inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed below.
The following examples are for illustrative purposes only and are not intended, nor
should they be construed to limit the invention in any way.

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EXAMPLES

All reactions were performed in flame-dried or oven-dried glassware under a positive
pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise
indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and
5 introduced into reaction vessels through rubber septa. Unless otherwise stated, the term
'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at
approximately 15 mrnHg. Unless otherwise stated, the term 'under high vacuum' refers to
a vacuum of 0.4 —1.0 mmHg.

10 All temperatures are reported in degrees Celsius (°C). Unless otherwise indicated, all
parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification. iV-
cyclohexyl-A'''-(methylpolystyrene)carbodiimide was purchased from Calbiochem-

15 Novabiochem Corp. 5-(Trifluoromethyl)-2-aminopyridine, 3-aminoqunioline, 3-
aminoisoquinoline, l-(4-methylpiperazinyl)-3-aminoisoquinoline, ethyl 4-
isocyanatobenzoate, A/-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline, 4-(4-
nitrobenzyl)pyridine, 4-phenoxyaniline, 4-(4-methylphenoxy)aniline, 4-(4-
chlorophenoxy) aniline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased

20 and used without further purification. Syntheses of 2-amino-4-ter^butylpyridine (C.K.
Esser et al. WO 96/18616; CJ. Donahue et al. Inorg. Chem. 30, 1991, 1588), 3-amino-2-
methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg.
Med. Chem.. 3, 1995, 129), 4-(3-carbamoylphenoxy)- 1 -nitrobenzene (K. Dcawa Yakugaku
Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 4-[(4-

25 methoxyphenyl)methylamino]aniline (P. Brermeisen et al. US 3,755,406; IBID US
3,839,582; IBID DE 1,935,388), 4-(4-pyridylcarbonyl)aniline (M.L. Carmello et al.
Pestic. Sci. 45, 1995, 227), 3-tert-butylphenyl isocyanate (O. Rohr et al. DE 2,436,108)
and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (K. rnukai et al. JP 42,025,067;
IBID Kogyo Kagaku Zasshi 70, 1967, 491) have, previously been described.

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Thin-layer chromatography (TLC) was performed using Whatman pre-coated glass-
backed silica gel 60 A F-254 250 um plates. Visualization of plates was effected by one
or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine
vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol
5 followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by
heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-
dinitrophenylhydrazine followed by heating. Column chromatography (flash
chromatography) was performed using 230-400 mesh EM Science® silica gel.

10 Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or
a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform
infrared sprectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a General
Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (5 0.00) or residual

15 protonated solvent (CHC1 3 5 7.26; MeOH 6 3.30; DMSO 6 2.49) as standard. Carbon
( 13 C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz)
spectrometer with solvent (CDC1 3 8 77.0; MeOD-d 3 ; 8 49.0; DMSO-d 6 8 39.5) as
standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS)
were either obtained as electron impact (EI) mass spectra or as fast atom bombardment

20 (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained, with a
Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption
Chemical Icnizaf.ion-Probe for sample introduction. The ion source was maintained at
250 °C. Electron impact ionization was performed with electron energy of 70 eV and a
trap current of 300 uA. Liquid-Cesium secondary ion mass spectra (FAB-MS), an

25 updated version of fast atom bombardment were obtained using a Kratos Concept 1-H
spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett
Packard MS -Engine (5 98 9 A) with methane or ammonia as the reagent gas (lxlO" 4 torr to
2.5x1 0" 4 torr). The direct insertion desorption chemical ionization (DCI) probe
(Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all

30 traces of the sample disappeared ( ~l-2 min). Spectra were scanned from 50-800 amu at 2
sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a

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Hewlett-Packard 1 100 HPLC equipped with a quaternary pump, a variable wavelength
detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with
electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion
time according to the number of ions in the source. Gas chromatography - ion selective
5 mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph
equipped with an HP-1 methyl silicone column (0.33 rnM coating; 25 m x 0.2 mm) and a
Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental
analyses were conducted by Robertson Microlit Labs, Madison NJ.

10 All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS
consistant with assigned structures.

List of Abbreviations and Acronyms:

AcOH

acetic acid

15

anh

anhydrous

atm

atmosphere(s)

BOC

/CTt-butoxycarbonyl

GDI

l,l'-carbonyl diimidazole

cone

concentrated

20

dec

decomposition

DMAC

7V,7V-dimethylacetamide

DMPU. .

. L3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone

DMF

. /V.Af-dimethylfoimamide .

DMSO

dimethylsulfoxide

25

DPPA

diphenylphosphoryl azide

EDCI

l-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EtOAc

ethyl acetate

EtOH

ethanol (100%)

Et 2 0

diethyl ether

30

Et 3 N

triethylamine

HOBT

1 -hydroxybenzotriazole

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m-CPBA

3-chloroperoxybenzoic acid

MeOH

methanol

pet. ether

petroleum ether (boiling range 30-60 °C)

THF

tetrahydrofuran

TFA

trifluoroacetic acid

Tf

trifluoromethanesulfonyl

A. General Methods for Synthesis of Substituted Anilines

Al. General Method for Substituted Aniline Formation via Hydrogenation of a
10 Nitroarene

4-(4-Pyridinylmethyl)aniIine: To a solution of 4-(4-nitrobenzyl)pyridine (7.0 g, 32.68
mmol) in EtOH (200 mL) was added 10% Pd/C (0.7 g) and the resulting slurry was
shaken under a H2 atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and 'H-NMR
15 of an aliquot indicated complete reaction. The mixture was filtered through a short pad of
Celite®. The filtrate was concentrated in vacuo to afford a white solid (5.4 g, 90%): 1 H-
NMR (DMSO-d 6 ) 6 3.74 (s, 2H), 4.91 (br s, 2H), 6.48 (d, .7=8.46 Hz, 2H), 6.86 (d, J=8.09
Hz, 2H), 7.16 (d, .7=5.88 Hz, 2H), 8.40 (d, J=5.88 Hz, 2H); EI-MS m/z 184 (M+). This
material was used in urea formation reactions without further purification.

20

A2. General Method for Substituted Aniline Formation via Dissolving Metal
Reduction of a Nitroarene

4-(2-Pyridinylthio)aniline: To a solution of 4-(2-pyridinylthio)-l -nitrobenzene (Menai
25 ST 3355A; 0.220 g, 0.95 mmol) and H2O (0.5 mL) in AcOH ( 5 mL) was added iron
powder (0.317 g 3 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The
reaction mixture was diluted with EtOAc (75 mL) and H2O (50 mL), basified to pH 10 by

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adding solid K2CO3 in portions {Caution: foaming). The organic layer was washed with a
saturated NaCl solution, dried (MgS04), concentrated in vacuo. The residual solid was
purified by MPLC (30% EtOAc/70% hexane) to give the desired product as a thick oil
(0.135 g, 70%): TLC (30% EtOAc/70% hexanes) R/0.20.

A3 a. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. l-Methoxy-4-(4-nitrophenoxy)benzene: To a suspension of NaH.(95%, 1.50 g,
10 59 mmol) in DMF (100 mL) at room temp, was added dropwise a solution of 4-

methoxyphenol (7.39 g, 59 mmol) in DMF (50 mL). The reaction was stirred 1 h, then a
solution of 1 -fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added
dropwise to form a dark green solution. The reaction was heated at 95 °C overnight, then
cooled to room temp., quenched with H2O, and concentrated in vacuo. The residue was
15 partitioned between EtOAc (200 mL) and H2O (200 mL). The organic layer was

sequentially washed with H2O (2 x 200 mL), a saturated NaHCC>3 solution (200 mL), and
a saturated NaCl solution (200 mL), dried (Na 2 S04), and concentrated in vacuo. The
residue was triturated (Et 2 0/hexane) to afford l-methoxy-4-(4-nitrophenoxy)benzene

(12.2 g, 100%): 'H-NMR (CDCI3) 6 3.83 (s, 3H), 6.93-7.04 (m, 6H), 8.18 (d, J-9.2 Hz,
20 2H); EI-MS m/z 245 (M + ).

Step 2. 4-(4-Methoxyphenoxy) aniline: To a solution of l-methoxy-4-(4-
nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C (1.5 g)
25 and the resulting slurry was shaken under a H2 atmosphere (50 psi) for 1 8 h. The reaction
mixture was filtered through a pad of Celite® with the aid of EtOAc and concentrated in
vacuo to give an oil which slowly solidified (10.6 g, 100%): 'H-1S1MR (CDC1 3 ) 5 3.54 (br
s, 2H), 3.78 (s, 3H), 6.65 (d, .7=8.8 Hz, 2H), 6.79-6.92 (m, 6H); EI-MS m/z 215 (M + ).

5

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A3b. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

5 Step 1. 3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4-

mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles),
and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred at
room temperature and under argon overnight. TLC showed complete reaction. The
mixture was diluted with Et^O (100 mL) and water (100 mL) and the aqueous layer was
10 back-extracted with Et-20 (2 x 100 mL). The organic layers were washed with a saturated
NaCl solution (100 mL), dried (MgSC^X and concentrated under reduced pressure. The
solid residue was triturated with E12O to afford the desired product as a tan solid (3.8 g,
54%): TLC (30% EtOAc/70% hexane) R/0.06; 'H-NMR (DMSO-d 6 ) 6 7.33 (dd, ,7=1,2,
4.2 Hz, 2H), 7.78 (d, 7=8.7 Hz, 1H), 8.46 (dd, 7=2.4, 8.7Hz, 1H), 8.54-8.56 (m, 3H).

15

Step 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniIine: A slurry of 3-trifluoromethyl-
4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 g, 71.6 mmol),
acetic acid (100 mL), and water (1 mL) were stirred at room temp, for 4 h. -The mixture
was diluted with Et 2 0 (100 mL) and water (100 mL). The aqueous phase was adjusted to

20 pH 4 with a 4 N NaOLT solution. The combined organic layers were washed with a
saturated NaCl solution (100 mL), dried (MgS04), and concentrated under reduced
pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50%
hexane to 60% EtO Ac/40% hexane) to afford the desired product (3.3 g): TLC (50%
EtOAc/50% hexane) R/0.10; l H-NMR (DMSO-d 6 ) 5 6.21 (s, 2H), 6.84-6.87 (m, 3H),

25 7.10 (d, 7=2.4 Hz, 1H), 7.39 (d, 7=8.4 Hz, 1H), 8.29 (d, 7=6.3 Hz, 2H).

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A3c. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

0,N

Step 1. 4-(2 (4-Phenyl)thiazolyl)thio-l-nitrobenzene: A solution of 2-mercapto-4-
5 phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with l-fluoro-4-
nitrobenzene (2.3 mL, 21.7 mmoles) followed by K 2 C0 3 (3.18 g, 23 mmol), and the
mixture was heated at approximately 65 °C overnight. The reaction mixture was then
diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated
NaCl solution (100 mL), dried (MgSCU) and concentrated under reduced pressure. The
10 solid residue was triturated with a Et 2 0/hexane solution to afford the desired product (6.1
g): TLC (25% EtOAc/75% hexane) R/0.49; 'H-NMR (CDC1 3 ) 5 7.35-7.47 (m, 3H), 7.58-
7.63 (m, 3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).

Step 2. 4-(2-(4-Phenyl)thiazolyl)thioaniline: 4-(2-(4-Phenyl)thiazolyl)thio-l-nitro-
15 benzene was reduced in a manner analagous to that used in the preparation of 3-

(trifluoromethyl)-4-(4-pyridinylthio)aniline: TLC (25% EtOAc/75% hexane) R/0.18; ! H-
NMR (CDCI3) 6 3.89 (br s, 2H), 6.72-6.77 (m, 2H), 7.26-7!53(m^ 6H), 7.85-7.89 (m, 2H).

A3d. General Method for Substituted Aniline Formation via Nitroarene Formation
20 Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 4-(6-Methyl-3-pyridinyloxy)-l-nitrobenzene: To a solution of 5-hydroxy-2-
methylpyridine (5.0 g, 45.8 mmol) and l-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh

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DMF (50 mL) was added K 2 C0 3 (13.0 g, 91.6 mmol) in one portion. The mixture was
heated at the reflux temp, with stirring for 18 h and then allowed to cool to room temp.
The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150
mL). The combined organics were sequentially washed with water (3 x 100 mL) and a
5 saturated NaCl solution (2 x 100 mL), dried (Na 2 S0 4 ), and concentrated in vacuo to

afford the desired product (8.7 g, 83%). This material was carried to the next step without
further purification.

10 pyridinyloxy)-l -nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to 10%
Pd/C (0.500 g, 0.47 mmol) and the resulting mixture was placed under a H 2 atmosphere
(balloon) and was allowed to stir for 1 8 h at room temp. The mixture was then filtered
through a pad of Celite® and concentrated in vacuo to afford the desired product as a tan
solid (3.2 g, 92%): EI-MS m/z 200 (M+).

A3e. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 4-(3,4-Dimethoxyphenoxy)-l-nitrobenzene: To a solution of 3,4-
20 dimethoxyphenol (1.0 g, 6.4 mmol) and l-fluoro-4-nitrobenzene (700 uL, 6.4 mmol) in

anh DMF (20 mL) was added K 2 C0 3 (1.8 g, 12.9 mmol) in one portion. The mixture was

heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp.

The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100

mL). The combined organics were sequentially washed with water (3x50 mL) and a
25 saturated NaCl solution (2 x 50 mL), dried (Na 2 S0 4 ), and concentrated in vacuo to afford

the desired product (0.8 g, 54%). The crude product was carried to the next step without

fiirther purification.

Step 2.

4-(6-Methyl-3-pyridinyloxy)aniline: A solution of 4-(6-methyl-3-

15

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H 2 N OMe
Step 2. 4-(3,4-Dimethoxyphenoxy)aniline: A solution of 4-(3,4-dimethoxy-phenoxy)-l-
nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and
the resulting mixture was placed under a H 2 atmosphere (balloon) and was allowed to stir
for 18 h at room temp. The mixture was then filtered through a pad of Celite® and
concentrated in vacuo to afford the desired product as a white solid (0.6 g, 75%): EI-MS
m/z 245 (M 4 ).

A3f. General Method for Substituted Aniline Formation via Nitroarene Formation
10 Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine (2.8 g,
29.0 mmol), l-bromo-3 -nitrobenzene (5.9 g, 29.0 mmol) and copper(I) bromide (5.0 g,
34.8 mmol) in aria DMF (50 mL) was added K 2 C0 3 (8.0 g, 58.1 mmol) in one portion.

15 The resulting mixture was heated at the reflux temp, with stirring for 18 h and then
allowed to cool to room temp. The mixture was then poured into water (200 mL) and
extracted with EtOAc (3x150 mL). The combined organics were sequentially washed
with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na 2 S0 4 ), and
concentrated in vacuo. The resulting oil was purified by flash chromatography (30%

20 EtO Ac/70% hexane) to afford the desired product (2.0 g, 32 %). This material was used
in the next step without further purification.

Step 2. 3-(3-Pyridinyloxy)aniline: A solution of 3-(3-pyridinyloxy)-l-nitrobenzene
(2.0 g, 9.2 mmol) in EtOAc (100 mL) was added to 10% Pd/C (0.200 g) and the resulting
25 mixture was placed under a H 2 atmosphere (balloon) and was allowed to stir for 1 8 h at
room temp. The mixture was then filtered through a pad of Celite® and concentrated in
vacuo to afford the desired product as a red oil (1 .6 g, 94%): EI-MS m/z 1 86 (M + ).

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A3g. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

5 Step 1. 3-(5-Methyl-3-pyridinyloxy)-l -nitrobenzene: To a solution of 3-hydroxy-5-
methylpyridine (5.0 g, 45.8 mmol), l-bromo-3 -nitrobenzene (12.0 g, 59.6 mmol) and
copper(T) iodide (10.0 g, 73.3 mmol) in anh DMF (50 mL) was added K 2 C0 3 (13.0 g, 91.6
mmol) in one portion. The mixture was heated at the reflux temp, with stirring for 18 h
and then allowed to cool to room temp. The mixture was then poured into water (200
10 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially
washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried
(Na2SC>4), and- concentrated in vacuo . The resulting oil was purified by flash
chromatography (30% EtO Ac/70% hexane) to afford the desired product (1.2 g, 13%).

15 Step 2. 3-(5-Methyl-3-pyridmyloxy)-l-nitrobenzene: A solution of 3-(5-methyl-3-
pyridinyloxy)-l -nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to 10%
Pd/C (0.100 g) and the resulting mixture was placed under a H2 atmosphere (balloon) and
was allowed to stir for 1 8 h at room temp. The mixture was then filtered through a pad of
Celite® and concentrated in vacuo to afford the desired product as a red oil (0.9 g, 86%):

20 CI-MS m/z 201 ((M+H) + ).

A3h. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

25 Step 1. 5-Nitro-2-(4-methylphenoxy)pyridine: To a solution of 2-chloro-5-

nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were added of 4-methylphenol (5.4 g,
50 mmol, 1.25 equiv) and K2CO3 (8.28 g, 60 mmol, 1.5 equiv). The mixture was stirred

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overnight at room temp. The resulting mixture was treated with water (600 mL) to
generate a precipitate. This mixture was stirred for 1 h, and the solids were separated and
sequentially washed with a 1 N NaOH solution (25 mL), water (25 mL) and pet ether (25
mL) to give the desired product (7.05 g, 76%): mp 80-82 °C; TLC (30% EtOAc/70% pet
5 ether) R/0.79; 'H-NMR (DMSO-d 6 ) 5 2.31 (s, 3H), 7.08 (d, .7=8.46 Hz, 2H), 7.19 (d,
.7=9.20 Hz, 1H), 7.24 (d, .7=8.09 Hz, 2H), 8.58 (dd, 7=2.94, 8.82 Hz, 1H), 8.99 (d, .7=2.95
Hz, 1H); FAB-MS m/z (rel abundance) 231 ((M+H) + ), 100%).

Step 2. 5-Amino-2-(4-methylphenoxy)pyridine Dihydrochloride: A solution 5-nitro-
10 2-(4-methylphenoxy)pyridine (6.94 g, 30 mmol, 1 eq) and EtOH (10 mL) in EtOAc (190
mL) was purged with argon then treated with 10% Pd/C (0.60 g). The reaction mixture
was then placed under a H 2 atmosphere and was vigorously stirred for 2.5 h. The reaction
mixture was filtered through a pad of Celite®. A solution of HC1 in Et20 was added to the
filtrate was added dropwise. The resulting precipitate was separated and washed with
15 EtOAc to give the desired product (7.56 g, 92%): mp 208-210 °C (dec); TLC (50%

EtOAc/50% pet ether) R/0.42; ! H-NMR (DMSO-d 6 ) 2.25 (s, 3H), 6.98 (d, .7=8.45 Hz,
2H), 7.04 (d, .7=8.82 Hz, 1H), 7.19 (d, .7=8.09 Hz, 2H), 8.46 (dd, J=2.57, 8.46 Hz, 1H),
8.63 (d, J=2.57 Hz, 1H); EI-MS m/z (rel abundance) (M + , 100%).

20 A3i. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 4-(3-Thienylthio)-l-nitrobenzene: To a solution of 4-nitrothiophenol (80%pure;
1.2 g, 6.1 mmol), 3-bromothiophene (1.0 g, 6.1 mmol) and copper(n) oxide (0.5 g, 3.7
25 mmol) in anhydrous DMF (20 mL) was added KOH (0.3 g, 6.1 mmol), and the resulting
mixture was heated at 130 °C with stirring for 42 h and then allowed to cool to room

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temp. The reaction mixture was then poured into a mixture of ice and a 6N HC1 solution
(200 mL) and the resulting aqueous mixture was extracted with EtOAc (3 x 1 00 mL). The
combined organic layers were sequentially washed with a 1M NaOH solution (2 x 100
mL) and a saturated NaCl solution (2 x 100 mL), dried (MgSC>4), and concentrated in
vacuo . The residual oil was purified by MPLC (silica gel; gradient from 1 0%
EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g,
34%). GC-MS miz 237 (M 4 ").

Step 2. 4-(3-Thienylthio)anilme: 4-(3-Thienylthio)-l -nitrobenzene was reduced to the
aniline in a manner analogous to that described in Method Al .

A3j. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

4-(5-Pyrimininyloxy)aniline: 4-Aminophenol (1 .0 g, 9.2 mmol) was dissolved in DMF
(20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2CO3 (1.9 g, 13.7 mmol) were
added. The mixture was heated to 100 °C for 18 h and at 130 °C for 48 h at which GC-
MS analysis indicated some remaining starting material. The reaction mixture was cooled
to room temp, and diluted with water (50 mL). The restilting solution was extracted with
EtOAc (1 00 mL). The organic layer was washed with a saturated NaCl solution (2x50
mL), dried (MgS04), and concentrated in vacuo. The residual solids were purified by
MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%).

A3 k. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction

Br — <f 7— OMe

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Step 1. 5-Bromo-2-rnethoxypyridine: A mixture of 2,5-dibromopyridine (5.5 g, 23.2
mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed
reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was
treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined
5 organic layers were dried (Na2SC>4) and concentrated under reduced pressure to give a
pale yellow, volatile oil (4.1g, 95% yield): TLC (10% EtOAc / 90% hexane) R/0.57.

HO-/ y—OUe

Step 2. 5-Hydroxy-2-methoxypyridine: To a stirred solution of 5-bromo-2-
methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78 °C was added an n-

10 butyllithium solution (2.5 M in hexane; 28.7 mL, 71 .8 mmol) drop wise and the resulting
mixture was allowed to stir at -78 °C for 45 min. Trimethyl borate (7.06 mL, 62.2 mmol)
was added via syringe and the resulting mixture was stirred for an additional 2 h. The
bright orange reaction mixture was warmed to 0 °C and was treated with a mixture of a 3
N NaOH solution (25 mL, 71 .77 mmol) and a hydrogen peroxide solution (30%; approx.

15 50 mL). The resulting yellow and slightly turbid reaction mixture was warmed to room
temp, for 30 min and then heated to the reflux temp, for 1 h. The reaction mixture was
then allowed to cool to room temp. The aqueous layer was neutralized with a IN HC1
solution then extracted with Et20 (2 x 100 mL). The combined organic layers were dried
(Na2SC>4) and concentrated under reduced pressure to give a viscous yellow oil (3.5g,

20 60%).

OMe

Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-l-nitrobenzene: To a stirred slurry of NaH
(97%, 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2-
methoxypyridme (3.5g, 28 mmol) in DMF (100 mL). The resulting mixture was allowed
25 to stir at room temp, for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via

syringe. The reaction mixture was heated to 95 °C overnight, then treated with water (25
mL) and extracted with EtOAc (2 x 75 mL). The organic layer was dried (MgSCU) and
concentrated under reduced pressure. The residual brown oil was crystalized
EtOAc/hexane) to afford yellow crystals (5.23 g, 75%).

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H 2 N ^ N OMe

Step 4. 4-(5-(2-Methoxy)pyridyl)oxyaniline: 4-(5-(2-Mefhoxy)pyridyl)oxy-l-
nitrobenzene was reduced to the aniline in a manner analogous to that described in
Method A3d, Step2.

A4a. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic
Substitution using a Halopyridine

H 2 N v S

3- (4-Pyridinylthio)aniline: To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles) in
10 anh DMF (90mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles)

followed by K2CO3 (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp,
for 1.5 h, then diluted with EtOAc (100 mL) and water (lOOmL). The aqueous layer was
back-extracted with EtOAc (2 x 100 mL). The combined organic layers were washed
with a saturated NaCl solution (100 mL), dried (MgSC>4), and concentrated under reduced
15 pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50%
hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a
Et 2 0/hexane solution to afford the desired product (4.6 g, 66%): TLC (100 % ethyl
acetate) R/0.29; 'H-NMR (DMSO-d 6 ) 6 5.41 (s, 2H), 6.64-6.74 (m, 3H), 7.01 (d, J=4.8,
2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, J=4.8, 2H).

20

A4b. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic
Substitution using a Halopyridine

4- (2-MethyI-4-pyridinyloxy)aniline: To a solution of 4-aminophenol (3.6 g, 32.8 mmol)
25 and 4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was added potassium tert-

butoxide (7.4 g, 65.6 mmol) in one portion. The reaction mixture was heated at 100 °C
with stirring for 18 h, then was allowed to cool to room temp. The resulting mixture was

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poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined
extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution
(2 x 100 mL), dried (NasSCU), and concentrated in vacuo. The resulting oil was purified
by flash chromatography (50 % EtOAc/50% hexane) to afford the desired product as a
5 yellow oil (0.7 g, 9%): CI-MS m/z 201 ((M+H) 4 ).

A4c. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic
Substitution using a Halopyridine

Step 1. Methyl(4-nitrophenyl)-4-pyridylamine: To a suspension of iV-methyl-4-
nitroaniline (2.0 g, 13.2 mmol) and K 2 C0 3 (7.2 g, 52.2 mmol) in DMPU (30mL) was
added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The reaction mixture was
heated at 90 °C for 20 h, then cooled to room temperature. The resulting mixture was
15 diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was
washed with water (100 mL), dried (NaaSO^O and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel, gradient from 80%
EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4-nitrophenyl)-4-pyridylamine
(0.42 g)

Step 2. Methyl(4-aminophenyl)-4-pyridylamine: Methyl(4-nitrophenyl)-4-
pyridylamine was reduced in a manner analogous to that described in Method Al.

A5. General Method of Substituted Aniline Synthesis via Phenol Alkylation
25 Followed by Reduction of a Nitroarene

Me

20

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Step 1. 4-(4-Butoxyphenyl)thio-l-nitrobenzene: To a solution of 4-(4-nitrophenyl-
thio)phenol (1.50 g, 6.07 mmol) in anh DMF (75 ml) at 0 °C was added NaH (60% in
mineral oil, 0.267 g, 6.67 mmol). The brown suspension was stirred at 0 °C until gas
5 evolution stopped (1 5 min), then a solution of iodobutane (1 . 12 g, .690 ml, 6.07 mmol) in
anh DMF (20 mL) was added dropwise over 15 min at 0 °C. The reaction was stirred at
room temp, for 18 h at which time TLC indicated the presence of unreacted phenol, and
additional iodobutane (56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv) and NaH (13 mg,
0.334 mmol) were added. The reaction was stirred an additional 6 h at room temp., then

10 was quenched by the addition of water (400 mL). The resulting mixture was extracted
with Et 2 0 (2 x 500 mL). The combined organics were washed with water (2 x 400 mL),
dried (MgS04), and concentrated under reduced pressure to give a clear yellow oil, which
was purified by silica gel chromatography (gradient from 20% EtOAc/80% hexane to
50% EtOAc/50% hexane) to give the product as a yellow solid (1.24 g, 67%): TLC (20%

15 EtO Ac/80% hexane) R/0.75; ! H-NMR (DMSO-d 6 ) 6 0.92 (t, J= 7.5 Hz, 3H), 1.42 (app
hex, y=7.5 Hz, 2H), 1.70 (m, 2H), 4.01 (t, J= 6.6 Hz, 2H), 7.08 (d, .7=8.7 Hz, 2H), 7.17
(d, J=9 Hz, 2H), 7.51 (d, J= 8.7 Hz, 2H), 8.09 (d, J= 9 Hz, 2H).

Step 2. 4-(4-Butoxyphenyl)thioaniline: 4-(4-Butoxyphenyl)thio-l -nitrobenzene was
20 reduced to the aniline in a manner analagous to that used in the preparation of 3-
(trifluoromethyl)-4-(4-pyridinylthio)aniline (Method A3b, Step 2): TLC (33%
EtO Ac/77% hexane) 0.38.

A6. General Method for Synthesis of Substituted Anilines by the Acylation of
25 Diaminoarenes

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4-(4-tert-Butoxycarbamoylbenzyl)aniline: To a solution of 4,4'-methylenedianiline
(3.00 g, 15.1 mmol) in anh THF (50 mL) at room temp was added a solution of di-tert-
butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction mixture was
heated at the reflux temp, for 3 h, at which time TLC indicated the presence of unreacted
5 methylenedianiline. Additional di-ferf -butyl dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv)
was added and the reaction stirred at the reflux temp, for 16 h. The resulting mixture was
diluted with Et 2 0 (200 mL), sequentially washed with a saturated NaHCOa solution (100
ml), water (100 mL) and a saturated NaCl solution (50 mL), dried (MgS04), and

concentrated under reduced pressure. The resulting white solid was purified by silica gel
10 chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to
afford the desired. product as a white solid ( 2.09 g, 46%): TLC (50% EtO Ac/50%
hexane) R/0.45; 'H-NMR (DMSO-d 6 ) 5 1.43 (s, 9H), 3.63 (s, 2H), 4.85 (br s, 2H), 6.44
(d, 7=8.4 Hz, 2H), 6.80 (d, J=8.1 Hz, 2H), 7.00 (d, .7=8.4 Hz, 2H), 7.28 (d, 7=8.1 Hz,
2H), 9.18 (br s, 1H); FAB-MS m/z 298 (M + ). .

15

A7. General Method for the Synthesis of Aryl Amines via Electrophilic Nitration
Followed by Reduction

Step 1. 3-(4-NitrobenzyI)pyridine: A solution of 3-benzylpyridine (4.0 g, 23.6

20 mmol) and 70% nitric acid (30 mL) was heated overnight at 50 °C. The resulting mixture
was allowed to cool to room temp, then poured into ice water (350 mL). The aqueous
mixture then made basic with a IN NaOH solution, then extracted with Et 2 0 (4 x 100
mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a
saturated NaCl solution (2 x 100 mL), dried (Na 2 S04), and concentrated in vacuo. The
25 residual oil was purified by MPLC (silica gel; 50 % EtOAc/50% hexane) then

recrystallization (EtOAc/hexane) to afford the desired product (1.0 g, 22%): GC-MS m/z
214 (M + ).

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Step 2. 3-(4-PyridinyI)metliylaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the
aniline in a manner analogous to that described in Method Al .

5 A8. General Method for Synthesis of Aryl Amines via Substitution with
Nitrobenzyl Halides Followed by Reduction

Step 1. 4-(l-Imidazolylmethyl)-l-nitrobenzene: To a solution of imidazole (0.5 g, 7.3
mmol) and 4-nitrobenzyl bromide (1 .6 g, 7.3 mmol) in anh acetonitrile (30 mL) was

10 added K2CO3 (1.0 g, 7.3 mmol). The resulting mixture was stirred at room temp, for 18 h
and then poured into water (200 mL) and the resulting aqueous solution was extracted
with EtOAc (3x 50 mL). The combined organic layers were sequentially washed with
water (3 x 50 mL) and a saturated NaCl solution (2 x 50 mL), dried (MgS04), and
concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 25%

15 EtOAc/75% hexane) to afford the desired product (1.0 g, 91%): EI-MS m/z 203 (M + ).

Step 2. 4-(l-Imidazolylmethyl)aniline: 4-(l-Imidazolylmethyl)-l -nitrobenzene was
reduced to the aniline in a manner analogous to that described in Method A2.

20 A9. Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl
Compounds Followed by Reduction

OH

Step 1. 4-(l-Hydroxy-l-(4-pyridyl)methyl-l -nitrobenzene: To a stirred solution of 3-
(4-nitrobenzyl)pyridine (6.0 g, 28 mmol) in CH 2 C1 2 (90 mL) was added ?n-CPBA (5.80 g,

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33.6 mmol) at 10 °C, and the mixture was stirred at room temp, overnight. The reaction
mixture was successively washed with a 10% NaHSC>3 solution (50 mL), a saturated
K 2 C0 3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgS0 4 ) and
concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolved in
5 anh acetic anhydride (30 mL) and heated at the reflux temperature overnight. The mixture
was concentrated under reduced pressure. The residue was dissolved in MeOH (25 mL)
and treated with a 20% aqueous NH3 solution (30 mL). The mixture was stirred at room
temp, for 1 h, then was concentrated under reduced pressure. The residue was poured into
a mixture of water (50 mL) and CH 2 C1 2 (50 mL). The organic layer was dried (MgSCU),
10 concentrated tinder reduced pressure, and purified by column chromatography (80%

EtOAc/ 20% hexane) to afford the desired product as a white solid. (0.53 g, 8%): mp 110-
118 °C; TLC (80% EtOAc/20% hexane) R/0.12; FAB-MS m/z 367 ((M+H) + , 100%).

OH

15 Step 2. 4-(l-Hydroxy-l-(4-pyridyl)methyIamIme: 4-( 1 -Hydroxy- l-(4-pyridyl)-methyl-
1 -nitrobenzene was reduced to the aniline in a manner analogous to that described in
Method A3d, Step2.

A10. Formation of 2-(iV-methylcarbamoyl)pyridines via the Menisci reaction

O

20

Step 1. 2-(/V-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous,
potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-
methylformamide (250 mL) under argon at ambient temp was added cone. H2SO4 (3.55
mL) (exotherm). To this was added H 2 0 2 (17 mL, 30% wt in H 2 0) followed by
25 FeS04'7H 2 0 (0.55 g) to produce an exotherm. The reaction was stirred in the dark at
ambient temp for lh then was heated slowly over 4 h at 45 °C. When bubbling
subsided,the reaction was heated at 60 °C for 16 h. The resulting opaque brown solution

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• was diluted with H 2 0 (700 mL) followed by a 10% NaOH solution (250 mL). The
resulting aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers
were washed separately with a saturated NaCl solution (3x150 mL). The combined
organics phases were dried (MgSO^ and filtered through a pad of silica gel eluting with
5 EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica
gel chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 20%
hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2-(7V-
methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50%
hexane) R/0.50; MS; l HNMR (CDC1 3 ): d 8.44 (d, 1 H, J = 5.1 Hz, CHN), 8.21 (s, 1H,
10 CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J = 2.4, 5.4 Hz, C1CHCN), 3.04 (d, 3H, J =
5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+).

Step lb. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via

1 5 Anhydrous DME (6.0 mL) was slowly added to SQC1 2 (180 mL) between 40° and 50 °C.
The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g,
487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C
(vigorous SO2 evolution) for 16 h to generate a yellow solid precipitate. The resulting
mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to

20 200 mL. The toluene addition/concentration process was repeated twice. The resulting
nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and
dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCI salt
as a yellow-orange solid (92.0 g, 89%).

Anh DMF (10.0 mL) was slowly added to SOCl 2 (300 mL) at 40-48 °C. The solution
was stirred at that temp, range for 10 min., then picolinic acid (100 g, 812 mmol) was
added over 30 min. The resulting solution was heated at 72 °C (vigorous SO2 evolution)
for 16 h to generate a yellow solid. The resulting mixture was 'cooled to room temp.,

picolinic acid

O

25 Step 2.

Synthesis of methyl 4-chIoropyridme-2-carboxyIate HCI salt

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diluted with toluene (500 mL) and concentrated to 200 mL. The toluene
addition/concentration process was repeated twice. The resulting nearly dry residue was
filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum
for 4 hours to afford 4-chloropyridine-2-carbonyl chloride HC1 salt as an off-white solid
5 (27.2 g, 16%). This material was set aside.

The red filtrate was added to MeOH (200 mL) at a rate which kept the internal
temperature below 55 °C. The contents were stirred at room temp, for 45 min., cooled to
5 °C and treated with Et 2 0 (200 mL) dropwise. The resulting solids were filtered,

10 washed with Et20 (200 mL) and dried under reduced pressure at 35 °C to provide methyl
4-chloropyridine-2-carboxylate HC1 salt as a white solid (1 10 g, 65%): mp 108-112 °C;
'H-NMR (DMSO-d 6 ) 5 3.88 (s, 3H); 7.82 (dd, .7=5.5, 2.2 Hz, 1H); 8.08 (d, .7=2.2 Hz,
1H); 8.68 (d, .7=5.5 Hz, 1H); 10.68 (br s, 1H); HPLC ES-MS m/z 172 ((M+H) + ).

A suspension of methyl 4-chloropyridine-2-carboxylate HC1 salt (89.0 g, 428 mmol) in
MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF .(1 L) at a
rate which kept the internal temp, below 5 °C. The resulting mixture was stored at 3 °C
20 for 5 h, then concentrated under reduced pressure. The resulting solids were suspended
in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500
mL), dried (Na2S04) and concentrated under reduced pressure to afford 4-chloro-iV-

methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; X H-
NMR (DMSO-de) 8 2.81 (s, 3H), 7.74 (dd, .7=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2, 1H), 8.61
25 (d, 7=5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m/z 171 ((M+H) + ).

O

15 Step 3a.

Synthesis of 4-chloro-A r -methyI-2-pyridinecarboxamide from methyl
4-chloropyridine-2-carboxylate

O

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25

Step 3b. Synthesis of 4-chloro-A r -methyl-2-pyridinecarboxamide from 4-
chloropyridine-2-carbonyl chloride

4-Chloropyridine-2-carbonyl chloride HC1 salt (7.0 g, 32.95 mmol) was added in portions
to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0
°C. The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced
pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and
filtered. The filtrate was washed with a saturated NaCl solution (2 x 100 mL), dried
(Na 2 SC>4) and concentrated under reduced pressure to provide 4-chloro-A r -methyl-2-
pyridmecarboxamide' as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 °C.

O

10 H * N

NHMe

Step 4. Synthesis of 4-(2-(iV-niethylcarbamoyl)-4-pyridyIoxy)aniline

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated
with potassium fert-butoxide (10.29 g, 91 .7 mmol), and the reddish-brown mixture was
stirred at room temp, for 2 h. The contents were treated with 4-chloro-iV-methyl-2-

15 pyridinecarboxamide (15.0 g, 87.9 mmol) and K2CO3 (6.50 g, 47.0 mmol) and then

heated at 80 °C for 8 h. The mixture was cooled to room temp, and separated between
EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-
extracted with EtOAc (300 mL). The combined organic layers were washed with a
saturated NaCl solution (4 x 1000 mL), dried (Na2S04) and concentrated under reduced

20 pressure. The resulting solids were dried under reduced pressure at 35 °C for 3 h to
afford 4-(2-(A^-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g,
84%): 'H-NMR (DMSO-d 6 ) 5 2.77 (d, .7=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86
(AA'BB' quartet, .7=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H),
8.44 (d, J=5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H) + ).

All. General Method for the Synthesis of 5-(4-Ammophenoxy)isoindoline-

1,3-dione

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O

O

Step 1. Synthesis of 5-hydroxyisoindoIine-l,3-dione

To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in cone. AcOH (25 mL) was
slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was
5 heated at 120 °C for 45 min., then 'the clear, bright yellow mixture was heated at 1 60 °C
for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to
approximately 15 mL, then was cooled to room temp, and adjusted pH 10 with a IN
NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a IN
HC1 solution. The resultant precipitate was collected by filtration and dried under
10 reduced pressure to yield 5-hydroxyisoindoline-l,3-dione as a pale yellow powder as

product (3.24 g, 72%): *H NMR (DMSO-d 6 ) 5 7.00-7.03 (m, 2H), 7.56 (d, J=9.3Hz, 1H).

Step 2. Synthesis of 5-(4~nitrophenoxy)isoindoline-l,3-dione

15 To a stirring slurry of NaH (1 .1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a
solution of 5-hydroxyisoindoline-l,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL)
dropwise. The bright yellow-green mixture was allowed to return to room temp, and was
stirred for 1 h, then l-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in
3-4 portions. The resulting mixture was heated at 70 °C overnight, then cooled to room

20 temp, and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 1 00 mL).
. The combined organic layers were dried (MgS04) and concentrated under reduced
pressure to give 5-(4-nitrophenoxy)isoindoline-l,3-dione as a yellow solid (3.3 g, 62%):
TLC (30% EtO Ac/70% hexane) R r 0.28; 1H NMR (DMSO-d 6 ) 5 7.32 (d, J=12 Hz, 2H),
7.52-7.57 (m, 2H), 7.89(d, .7=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 1 1.43 (br s, 1H); CI-MS

25 m/z 285 ((M+H) + , 100%).

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Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-l,3-dione

A solution of 5-(4-nitrophenoxy)isoindoline-l,3-dione (0.6 g, 2.11 mmol) in cone. AcOH
(12 mL) and water (0.1 ml) was stirred under stream of argon while iron powder (0.59 g,
5 55.9 mmol) was added slowly. This mixture stirred at room temp, for 72 h, then was
diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined
organic layers were dried (MgS04) and concentrated under reduced pressure to give 5-(4-
aminophenoxy)isoindoline-l,3-dione as a brownish solid (0.4 g, 75%): TLC (50%
EtOAc/50% hexane) R/0.27; 'HNMR (DMSO-d 6 ) 5 5.14 (br s, 2H), 6.62 (d, .7=8.7 Hz,
10 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, .7=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J=8A Hz,
1H), 1 1.02 (s, 1H); HPLC ES-MS m/z 255 ((M+H) + , 100%).

A12. General Method for the Synthesis of S-Sulfonylphenyl Anilines

15 Step 1. 4-(4-MethylsuIfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4-

methylthiophenoxy)-l-ntirobenzene (2 g, 7.66 mmol) in CH 2 C1 2 (75 mL) at 0 °C was
slowly added otCPBA (57-86%, 4 g), and the reaction mixture was stirred at room
temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution (25 mL).
The organic' layer was sequentially washed with a IN NaOH solution (25 mL), water (25

20 mL) and a saturated NaCl solution (25 mL), dried (MgS04), and concentrated under

reduced pressure to give 4-(4-methylsulfonylphenoxy)-l -nitrobenzene as a solid (2.1 g).

Step 2. 4-(4-Methylsulfonylphenoxy)-l-aniline: 4-(4-Methylsulfonylphenoxy)-l-
nitrobenzene was reduced to the aniline in a manner anaologous to that described in
25 Method A3d, step 2.

A13. General Method for Synthesis of 5-Alkoxy-6-carboxyphenyl Anilines

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Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: To a solution of
-(3-carboxy-4-hydroxyphenoxy)-l -nitrobenzene (prepared in a manner analogous to that
described in Method A3a, step 1, 12 rnmol) in acetone (50 mL) was added K 2 C0 3 (5 g)
5 and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temperature
overnight, then cooled to room temperature and filtered through a pad of Celite®. The
resulting solution was concentrated under reduced pressure, absorbed onto silica gel, and
purified by column chromatography (50% EtOAc / 50% hexane) to give 4-(3-
methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene as a yellow powder (3 g): mp 115-
10 118 °C.

O

Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3-
methoxycarbonyl-4-methoxyphenoxy)-l -nitrobenzene (1.2 g), KOH (0.33 g),and water (5
mL) in MeOH (45 mL) was stirred at room temperature overnight and then heated at the
15 reflux temperature for 4 h. The resulting mixture was cooled to room temperature and
concentrated under reduced pressure. The residue was dissolved in water (50 mL), and
the aqueous mixture was made acidic with a IN HC1 solution. The resulting mixture was
extracted with EtOAc (50 mL). The .organic Jayet. was dried (MgS0 4 ) and concentrated
under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l -nitrobenzene (1.04 g).

20

25

0 7 N

Step 3. 4-(3-(A , '-Methylcarbamoly)-4-methoxyphenoxy)-l-nitrdbenzene:

To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (0.50 g, 1.75 mmol) in
CH 2 C1 2 (12 mL) was added SOCl 2 (0.64 mL, 8.77 mmol) in portions. The resulting

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solution was heated at the reflux temp, for 18 h, cooled to room temp., and concentrated
under reduced pressure. The resulting yellow solids were dissolved in CH2CI2 (3 mL)
then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5
mL, 7.02 mrnoT) in portions (CAUTION: gas evolution), and stirred at room temp, for 4
5 h. The resulting mixture was treated with a IN NaOH solution, then extracted with

CH2CI2 (25 mL). The organic layer was dried (Na 2 S04) and concentrated under reduced
pressure to give 4-(3-(A r -methylcarbamoly)-4-methoxyphenoxy)-l -nitrobenzene as a
yellow solid (0.50 g, 95%).

O

10 Step 4. 4-(3-(iV-Methylcarbamoly)-4-methoxyphenoxy)aniline:

A slurry of 4-(3-(A/-methylcarbamoly)-4-methoxyphenoxy)-l -nitrobenzene (0.78 g, 2.60
mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under 1 arm of H 2 (balloon)
for 2.5 d, then was filtered through a pad of Celite®. The resulting solution was
concentrated under reduced pressure to afford 4-(3-(A r -methylcarbamoly)-4-
15 methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et 3 N/99.9%
EtOAc)R / 0.36.

A14. General Method for the Synthesis of 4-(3-iV-

20 Methylcarbamoylphenofy)anjlinec .

O -

Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-l -nitrobenzene

A mixture of 4-fluoro-l -nitrobenzene (16 mL, 150 mmol), ethyl 3 -hydroxybenz o ate 25 g,
150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux
25 temp, overnight, cooled to room temp, and treated with water (250 mL). The resulting
mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were
sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100

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mL), dried (Na 2 SC>4) and concentrated under reduced pressure. The residue was purified
by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-
ethoxycarbonylphenoxy)-! -nitrobenzene as an oil (38 g).

O

5 Step 2. Synthesis of 4-(3-carboxyphenoxy)-l -nitrobenzene

To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene (5.14 g,
17.9 irunol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH'HjO (1.50
g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight,
then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2
10 with a 1M HC1 solution. The resulting bright yellow solids were removed by filtration
and washed with hexane to give 4-(3-carboxyphenoxy)-l-nitrobenzene (4.40 g, 95%).

O

NHMe

Step 3. Synthesis of 4-(3-(Af-methylcarbamoyl)phenoxy)-l-nitrobenzene

A mixture of 4-(3-carboxyphenoxy)-l -nitrobenzene (3.72 g, 14.4 mmol), EDCI'HCl
15 ■ (3.63 g, 18.6 mmol), iV-methylrnorplioline (1.6 mL, 14.5 mmol) and methylamine (2.0 M
in THF; 8 mL, 16 mmol) in CH2CI2 (45 mL) was stirred at room temp, for 3 d, then
concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and
the resulting mixture was extracted 'vitb a 1M HC1 solution (50 mL). The aqueous layer
was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed
20 with a saturated NaCl solution (50 mL), dried (Na 2 S04), and concentrated under reduced
pressure to give 4-(3-(Af-methylcarbamoyl)phenoxy)-l -nitrobenzene as an oil (1.89 g).

O

NHMe

Step 4. Synthesis of 4-(3-(Af-methylcarbamoyl)phenoxy)aniline

A slurry of 4-(3-(7V-methylcarbamoyl)phenoxy)-l -nitrobenzene (1.89 g, 6.95 mmol) and
25 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H 2 atm (balloon) overnight.

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The resulting mixture was filtered through a pad of Celite and concentrated under
reduced pressure. The residue was purified by column chromatography (5% MeOH/95%
CH2CI2). The resulting oil solidified under vacuum overnight to give 4-(3-(7V-
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).

5

B. General Methods of Urea Formation

Bl. Reaction of a Heterocyclic Amine with an Aryl Isocyanate

H H

iV-(4-/er^-butylpyridyI)-iV , -(2,3-dichlorophenyl) urea: A solution of 2-amino-4-ter*-
10 butylpyridine (192 mg) and 2,3-dichlorophenyl isocyanate (240 mg) in anh. toluene (15
mL) was heated at 70 °C under argon for 24 h. The resulting mixture was diluted with
EtOAc (200 mL) then washed with water (125 mL). The organic layer was dried
(MgS04) and concentrated under reduced pressure to give a gum. Trituration of the gum
with hexanes afforded A 7 -(4-terif-butylpyridyl)-7^ -(2,3-dichlorophenyl) urea as a white
15 solid (394 mg, 91%): TLC (2:1 hexanes/ethyl acetate) R/ 0.40; FAB-MS m/z 338
((M+H) + ).

B2a. Reaction of a Heterocyclic Amine with iVjiV'-Carbonyldiimidazole Followed
by Reaction with a Substituted Aniline

O

N N N . .
20 H H

iV-(4-^^-butylpyridyl)-A^*-(4-(4-pyridinylmethyl)phenyl urea: To a stirring solution of
4-?ert-butyl-2-aminopyridine (192 mg) in anh. CH2CI2 (15 mL) under argon at 0 °C was
added CDI (207 mg). The resulting solution was allowed to warm to ambient temp over 2
h. To this mixture was added 4-(4-pyridylmethyl) aniline (prepared according to Method
25 Al, 235 mg). The resulting solution was stirred at room temperature for 24 h, then was

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quenched with water (125 mL). The resulting mixture was extracted with EtOAc (200
mL). The organic layer was washed with water (100 mL), dried (MgSCU) and
concentrated under reduced pressure. The residue was purified by chromatography (Si02,
EtOAc) to afford A r -(4-fer^butylpyridyl)-A^'-(4-(4-pyridinylmethyl)phenyl urea as a white
5 solid (200 mg, 43%): TLC (EtOAc) R/ 0.47; FAB-MS m/z 361 ((M+H) + ).

B2b. Reaction of a Heterocyclic Amine with A^iV'-Carbonyldiimidazole Followed
by Reaction with a Substituted Aniline

1Q A r ^V'-(Bis(3-(2-methoxyquinolinyl)) urea): To a stirring solution of 3-amino-2-

methoxyquinoline (138 mg) in anh CH 2 C1 2 (15 mL) under argon at 0 °C was added CDI
(128 mg). The resulting solution was warmed to ambient temp over 1 h. After 16 h 4-(2-
Af-Methylcarbamyl-4-pyridyloxy)aniline (175 mg) was added and the resulting yellow
solution was stirred at room temperature under argon for 72 h. The solution was treated

15 with water (125 mL) and the resulting mixture was extracted with EtOAc (2 x 150 mL).
The combined organics were washed with a saturated NaCl solution (100 mL), dried
(MgS04) and concentrated under reduced pressure. The residue was triturated with a 10%
hexane/90% EtOAc solution. The resulting white crystals were washed with EtOAc. The
resulting filtrate was purified by chromatography (Si0 2 , 50% EtOAc/50% hexane) to give

20 W-(bis(3-(2-methoxyquinol:nyl)) urea) (30 mg, 20% yield): TLC (50% EtOAc/50%
hexane) R/0.45: HPLC ES-MS m/z 375 ((M+H)~).

B2c. Reaction of a Heterocyclic Amine with iV,iV'-CarbonyldimiidazoIe Followed
by Reaction with a Substituted Aniline

25 H H

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jV_(4_^rt-Butylpyridyl)-iV'-(4-(4-chlorophenoxy)phenyl) urea: A solution of 4-tert-
butyl-2-aminopyridine (0.177 g, 1.18 mmol, 1 equiv.) in 1.2 mL of anh. CH 2 C1 2 (1.2 mL)
was added to CDI (0.200 g, 1.24 mmol, 1.05 equiv) and the mixture was allowed to stir
under argon at room temperature 1 d. To the resulting solution was added 4-(4-
5 chlorophenoxy)aniline (0.259 g, 1.18 mmol, 1 equiv.) in one portion. The resulting

mixture was stirred at room temperature for 1 d, then was treated with a 1 0% citric acid
solution (2 mL) and allowed to stir for 1 h. The resulting organic layer was extracted with
EtOAc (3x5 mL). The combined organic layers were dried (MgSCu) and concentrated in
vacuo. The residtant residue was treated with CH 2 C1 2 (10 mL) and a 1 N aqueous NaOH
10 solution. This mixture was allowed to stir overnight. The resulting organic layer was
extracted with CH 2 C1 2 (3x5 mL). The combined organic layers were (MgSCU) and
concentrated in vacuo. The resultant solids were suspended in diethyl ether (10 mL) and
sonicated for 1 5 minutes. The resulting white solids were dried to give N-{A-tert-
butylpyridyl)-/V"-(4-(4-chlorophenoxy)phenyl) urea (42 mg, 9%): mp 198-199 °C.

15

B3. Reaction of Substituted Aniline with A'i/y'-Carbonyldiiimdazole Followed by
Reaction with a Heterocyclic Amine

H H

JV-(2-(5-trifluoromethyl)pyridyloxy)-iV'-(3-(4-pyridylthio)phenyl) urea: A solution of
20 3-(4-pyridylthib)a'mMe "(300 mg, 1 .48 mmoles) in CH 2 C1 2 (12 mL) was treated with CDI
(253 mg, 1 .56 mmoles). The solution was stirred at room temperature and under argon
for 2 h. The resulting mixture was treated with 2-amino-5-(trifluoromethyl)pyridine (238
mg, 1 .47 mmoles) and heated at 40 °C overnight. The reaction mixture was then diluted
withEtOAc (25 mL), washed with water (10 mL) and a saturated NaCl solution m(25
25 mL), dried (MgSCu), and concentrated under reduced pressure. The residue was purified
by column chromatography (Si0 2 ; gradient from 70% EtOAc/30% CH 2 C1 2 to 100%
EtOAc to give 7Y-(2-(5-trifiuoromethyl)pyridyloxy)-iV''-(3-(4-pyridylthio)phenyl) urea
afforded (103 mg): TLC (50% EtOAc/50% CH 2 C1 2 ) R/0.33; 'H-NMR (DMSO-d 6 ) 6.06
(d, J=6Bz, 2H), 7.25 (dt, J=1.2,7.8 Hz, 1H), 7.48 (t, .7=8.1 Hz, 1H), 7.59-7.63 (m, 1H),

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7.77 (d, 7=8.7 Hz, 1H), 7.86 (t, 7=1.8 Hz, 1H), 8.12 (dd, 7=2.7,9.3 Hz, 1H), 8.37 (d, 7=6.3
Hz, 2H), 8.67 (bs, 1H), 9.88 (s, 1H), 10.26 (s, 1 H); FAB-MS m/z 391 ((M+H) + ).

B4. Reaction of a Heterocyclic Amine with Phosgene, Followed by Reaction "with
5 a Substituted Aniline

H H

A r -(3-(2-methoxyquinolinyl)-A r, -(4-(4-(2-A' : -Methylcarbamyl-4-pyridyloxy)phenyl)
urea: To a stirring solution of phosgene (20% in toluene, 1.38 mL) in anh. CH2CI2 (20
ml) at 0 °C under argon was added anh. pyridine (207 mg) followed by 3-amino-2-

10 methoxyquinoline (456 mg). The resulting solution was warmed to ambient temperature
over 1 h, then concentrated in vacuo at ambient temperature to give a white solid. The
solid was dried under vacuum for 15 min then suspended in anh toluene (20 mL). To the
resulting slurry was added 4-(4-(2-(methylcarbamoyl)pyridyloxy)aniline (prepared
according to Method A2, 300 mg) and the reaction heated under argon at 80 °C for 20 h.

15 The resulting mixture was diluted with water (200 mL), then treated with a saturated
NaHC0 3 solution (10 mL) and extracted with EtOAc (2 x 300 mL). The combined
organic layers were washed with a saturated NaCl solution (100 mL), dried (MgS04) and
concentrated under reduced pressure. The solid yellow residue was purified by
chromatography (Si0 2 , gradient from 50% EtOAc/50% hexane to 100% EtOAc),

.20 followed bylecrystailization from diethyl ether and hexane to give A^(3-(2-

methoxyqiiinolinyl)-iV"'-(4-(4-(2-^/'-Methylcarbamyl-4-pyridyloxy)phenyl) urea as a white
solid (140 mg, 25%): TLC (EtOAc) R/0.52; FAB-MS m/z 430 ((M+H) 4 ).

B5a. Reaction of an Aniline with iV,iV'-Carbonyl Diimidazole Followed by

25 Addition of a Second Aniline.

MeHN

NHMe

H H

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Bis(4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea

To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH2CI2 (15
mL) at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room
temp, over 1 h then was stirred at room temp, for 16 h. The resulting mixture was treated
5 with 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow
solution stirred at room temp, for 72 h, then was treated with water (125 mL). The
resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined
organic phases were washed with a saturated NaCl solution (100 ml), dried (MgSC>4) and
concentrated under reduced pressure. The residue was triturated (90% EtO Ac/10%
10 hexane). The resulting white solids were collected by filtration and washed with EtOAc
to give bis(4-(2-(7V-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.081 g, 44%): TLC
(100% EtOAc) R/0.50; l H NMR (DMSO-d 6 ) 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m,
12H), 8.48 (d, J=5.4 Hz, 1H), 8.75 (d, J=4.8 Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/z
513 ((M+H) + ).

15

B5b. Reaction of an Isocyanate with an Aniline.

CF 3 "

1 H H
OMe

7V-(2-Methoxy-5-(trifluoromethyl)phenyI-A f '-(4-(l,3-dioxoisomdoIin-5-yloxy)phenyl)

. . . . Urea.

20 To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47

mmol) in CH2CI2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-l,3-dione (Method
A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture Was stirred for 12 h,
then was treated with CH2CI2 (10 mL) and MeOH (5 mL). The resulting mixture was
sequentially washed with a IN HC1 solution (15 mL) and a saturated NaCl solution (15

25 mL), dried (MgSCU) and concentrated under reduced pressure to afford iV-(2-methoxy-5-
(trifluoromethyl)phenyl-iV'-(4-(l,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid
(0.2 g, 96%): TLC (70% EtOAc/30% hexane) R/0.50; ! H NMR (DMSO-d 6 ) 3.95 (s,

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3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H),
9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M+H) + , 100%).

B6. Reaction of an Aniline with Phosgene Followed by Addition of a

5 Second Aniline.

H H

A r -(3-(2-methoxyquinolinyl)-iY'-(4-(4-(2-A ? -Methylcarbamyl-4-pyridyloxy)phenyl)
Urea

To a stirring solution of phosgene (20% in toluene, 1.38 mL) in anh. CH2CI2 (20 ml) at 0
10 °C under argon was added anh. pyridine (207 mg) followed by 3-amino-2-

methoxyquinoline (456 mg). The resulting solution was warmed to ambient temperature
over 1 h, then concentrated in vacuo at ambient temperature to give a white solid. The
solid was dried under vacuum for 15 min then suspended in anh toluene (20 mL). To the
resulting slurry was added 4-(4-(2-(methylcarbamoyl)pyridyloxy)aniline (prepared
15 according to Method A2, 300 mg) and the reaction heated under argon at 80 °C for 20 h.
The resulting mixture was diluted with water (200 mL), then treated with a saturated
NaHC0 3 solution (10 mL) and extracted with EtOAc (2 x 300 mL). The combined
organic layers were washed with a saturated NaCl solution (100 mL), dried (MgS04) and
concentrated under reduced pressure. The solid yellow residue was purified by
20 chromatography (Si0 2 , gradient from 50% EtO Ac/50% hexane to 100% EtOAc),
followed by recrystallization from diethyl ether and hexane to give iy-(3-(2-
methoxyquinolinyl)-iV'-(4-(4-(2-Ar-Methylcarbamyl-4-pyridyloxy)phenyl) urea as a white
solid (140 mg, 25%): TLC (EtOAc) R/0.52; FAB-MS m/z 430 ((M+H) + ).

25

SPECIFIC COMPOUND PREPARATIONS

Descriptions of the detailed preparative steps used to prepare the specific
compounds listed in Tables 1 -8 are provided below. Many of the compounds listed in the

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Tables can be synthesized following a variety of methods. The specific examples below
are therefore provided by way of illustration only and should not be construed to limit the
scope of the invention in any way.

5 Entry 1 : 4-tert-Butyl-2-aimnopyridine was reacted with 4-tolyl isocyanate according to
Method Bl to afford the urea.

' Entry 2: 4-tert-Butyl-2-ammopyridine was reacted with 4-fluorophenyl isocyanate
according to Method Bl to afford the urea.

10

Entry 3: A r -(4-z'er^Butylpyridinyl)-A'''-(2,3-dichlorophenyl) urea was prepared according
to Method Bl.

Entry 4: 4-^ert-Butyl-2-aminopyridine was reacted with 1-naphthyl isocyanate according
15 to Method Bl to afford the urea.

Entry 5: A r -(4-rerr-Butylpyridyl)-jV'-(4-(4-pyridinylmethyl)phenyl urea was prepared
according to Method B2a.

20 Entry 6: 4-ter£-Butyl-2-aminopyridine was reacted with 4-phenoxyaniline according to
Method B2c to afford the urea.

Entry 7: 4-ter^Butyl-2-aminopyridine was reacted with 4-(4-methylphenoxy)aniline
according to Method B2c to afford the urea.

25

Entry 8: 7V"-(4-tert-Butylpyridyl)-iV"-(4-(4-chlorophenoxy)phenyl) urea was prepared
according to Method B2c.

Entry 9: 4-tert-Buryl-2-aminopyridine was reacted with 4- (4-methoxyphenoxy) aniline
30 according to Method B2c to afford the urea.

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Entry 10: 4-(4-Aminophenoxy)pyridine was prepared starting from 4-hydroxypyridine
and l-bromo-3-nitrobenzene according to Method A3F. 4-tert-Butyl-2-aminopyridine
was reacted with 4-(4-aminophenoxy)pyridine according to Method B2a to afford the
urea.

5

Entry 1 1 : 4-(4-Pyridylthio)aniline was prepared starting from 4-aminothiophenol and 4-
chloropyridine hydrochloride according to Method A4a. 4-tert-Butyl-2-airrinopyridine
was reacted with 4-(4-pyridylthio)aniline according to Method B2c to afford the urea.

10 Entry 12: 4-(4-Pyridylthio)aniline was prepared starting from 4-aminothiophenol and 4-
chloropyridine hydrochloride according to' Method A4a. 4-tert-Butyl-2-aminopyridine
was reacted with 3-(4-pyridylthio)aniline according to Method B2c to afford the urea.

Entry 13: 2-Amino-5-(trifluoromethyl)pyridine and 4-(4-pyridylmethyl)aniline were
15 reacted according to Method B3 to afford the urea.

Entry 14: iV-(2-(5-Trifluoromethyl)pyridyloxy)-7^ -(3-(4-pyridylthio)phenyl) urea was
prepared according to Method B3.

20 Entry 15: 3-Aminoisoquinoline was reacted with 4-tolyl isocyanate according to Method
Bl to afford the urea.

Entry 16: 3-Aminoisoquinoline was reacted with 4-fiuorophenyl isocyanate according to
Method B 1 to afford the urea.

25

Entry 17: 3-Aminoisoquinoline was reacted with 2,3-dichlorophenyl isocyanate according
to Method Bl to afford the urea.

Entry 18: 3-Aminoisoquinoline was reacted with 1-naphthyl isocyanate according to
30 Method B 1 to afford the urea.

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Entry 19: 3-Aminoisoquinoline was reacted with 4-(4-pyridylmethyl)amline according to
Method B2a to afford the urea.

Entry 20: 4-(4-Aminophenoxy)pyridine was prepared starting from 4-hydroxypyridine .
5 and l-bromo-3 -nitrobenzene according to Method A3f. 3-Aminoisoquinoline was reacted
with 4-(4-aminophenoxy)pyridine according to Method B2a to afford the urea.

Entry 21: 3-Aminoquinoline and 4-(4-pyridylmethyl)aniline were reacted according to
Method B3 to afford the urea.

10 ,

Entry 22: A r ,A r '-(Bis(3-(2-methoxyquinolinyl)) urea) was prepared according to Method
B2b.

Entry 23:3-Amino-2-methoxyquinoline and 4-(4-pyridylmethyl)aniline were reacted
15 according to Method B3 to afford the urea.

Entry 24: 3-Amino-2-methoxyquinoline was reacted with 4-(4-pyridylcarbonyl)aniline
according to Method B4 to afford the urea.

20 Entry 25: 4-(4-Pyridyloxy)aniline was prepared starting from 4-hydroxypyridine and 1-
fluoro-4-nitrobenzene according to Method A3d. 3-Amino-2-methoxyquinoline was
reacted with 4-(4-pyridyloxy)aniline according to Method B2c to afford the, urea.

Entry 26: 3-Amino-2-methoxyquinoline was reacted with 4-((4-
25 methoxyphenyl)methylamino)aniline according to Method B4 to afford the urea.

Entry 27: 3-(4-Pyridylthio)aniline was prepared according to Method A4a. 3-Amino-2-
methoxyquinoline and 3-(4-pyridylmethyl)aniline were reacted according to Method B3
to afford the urea.

30

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Entry 28: 4-(4-Pyridyloxy)aniline was prepared starting from 4-hydroxypyridine and 1-
fluoro-4-nitrobenzene according to Method A3d. l-(4-Methylpiperazinyl)-3-
aminoisoquinoline was reacted with 4-(4-aminophenoxy)pyridine according to Method
B2a to afford the urea.

5

Entry 104: 4-(4-(2-(A''-Methylcarbamoyl)pyridyloxy)aniline was prepared according to
Method A10. 3-Amino-2-methoxyquinoline was reacted with 4-(4-(2-(iV-
methylcarbamoyl)pyridyloxy)aniline according to Method B4 to afford the urea.

10 Entry 1 05 : 4-(3-7V-Methylcarbamoylphenoxy)aniline was prepared according to Method
A14. 3-Amino-2-methoxyquinoline was reacted with 4-(3-iV-
methylcarbamoylphenoxy)aniline according to Method B4 to afford the urea.

Entry 106: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine
15 according to Method A 10, Step 3b. The resulting 4-chloro-iV-isopropyl~2-

pyridinecarboxamide was reacted with 4-aminophenol according to Method A10, Step 4
to give 4-(2-(iV-isopropylcarbamoyl)-4-pyridyloxy)aniline. 3-Amino-2-methoxyquinoline
was reacted with 4-(2-(A^-isopropylcarbarnoyl)-4-pyridyloxy)aniline according to Method
B5b to afford the urea.

20

Entry 107: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
according to Method A10, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxamide was reacted with 4-aminophenol according to Method A10, Step 4
using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. 4-(2-
25 Carbamoyl-4-pyridyloxy)aniline was reacted with 4-(2-(iV-isopropylcarbamoyl)-4-
pyridyloxy)aniline according to Method B6 to afford the urea.

Entryl08: 4-Chloro-iV-methyl-2-pyridhiecafboxamide was synthesized according to
Method A10, Step 3b. 4-Chloro-Af-methyl-2-pyridinecarboxamide was reacted with 4-
30 aminophenol according to Method A10, Step 4 using DMAC in place of DMF to give 4-
(2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline. 3-Amino-2-methoxyquinoline was

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reacted with 4-(2-(A r -methylcarbamoyl)-4-pyridyloxy)ariiline according to Method B6 to
afford the urea.

Entry 109: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia
5 according to Method A10, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-
pyridinecarboxarnide was reacted with 3-aminophenol according to Method A10, Step 4
using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. 3-Amino-2-
methoxyquinoline was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline according to
Method B6 to afford the urea.

10

Entryl 10: 4-Chloro-iV-methyl-2-pyridinecarboxamide, which was synthesized according
to Method A10, Step 3a, was reacted with 3-aminophenol according to Method A10, Step
4 using DMAC in place of DMF to give 3-(-2-(iV-methylcarbamoyl)-4-
pyridyloxy)aniline. 3-Amino-2-methoxyquinoline was reacted with 3-(-2-(N-
15 methylcarbamoyl)-4-pyridyloxy)aniline according to Method B6 to afford the urea.

Entry 111: 4-(4-(3-(A r -Methylcarbamoyl)-2-methoxyphenoxy)aniline was prepared
according to Method A13. 3-Amino-2-methoxyquinoline was reacted with 4-(4-(3-(JV-
Methylcarbamoyl)-2-methoxyphenoxy)aniline was according to Method B6 to afford the
20 urea.

Entry 112: 5-(4-Aminophenoxy)isoindoline-l,3-dione was prepared according to Method
All. 3-Amino-2-methoxyquinoline was reacted with 5-(4-Aminophenoxy)isoindoline-
1,3-dione was according to Method B5b to afford the urea.

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The following compounds have been synthesized according to the General Methods listed
above:

Table 1.

4-ter?-Butyl-2-pyridyl Ureas

N

H H

TLC

Mass Spec.

mp

TT C

OUiVCIlL

|_OUUivCJ

Entry

R

(°C)

(min.)

System

1

— (^ r ~^)— Me

0.51

33%
EtOAc/
67%
aexane

284

(M+H)+
(FAB)

2.

JJ /o

57%
biexane

LOO

(FAB)

3

CI CI

0.40

33%

338

EtOAc /

67%

hexane

(M+H)+
(FAB)

4

0.46

33%
EtOAc /
67%
hexane

320

(M+H)+
(FAB)

5

0.47

100%
EtOAc

361

(M+H)+
(FAB)

6

179-
180

0.58

5% MeOH
l 95%
CH2C12

362

(M+H)+
(FAB)

• 7

190-
191

0.46

5% MeOH
' 95%
CH2C12

376

(M+H)+
(FAB)

8

198 -

0.76

5% MeOH

396

199

' 95%
CH2C12

(M+H)+ .
(FAB)

9

189-
193

0.43

5% MeOH
' 95%
CH2C12

392

(M+H)+
(FAB)

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1 A

10

J

c

pi

U.4U

1 C\C\0/

EtOAc

(M+H)+
(FAB)

1 1
A i

J

0

212

j /o ivicwxi.

' 95%
CH2C12

(M+H)+

(HPLC

ES-MS)

12

0

o

196-
197

0.37

5% MeOH
' 95%
CH2C12

379 .

(M+H)+

(FAB)

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Table 2. 5-(Trifluoromethyl)-2-pyridyl Ureas

H H

Entry

mp
(°C)

HPLC
(min.)

TLC

TLC
Solvent
System

Mass Spec.
[Source]

13

JCTO

0.34

30%
acetone /
70%
CH2C12

373

(M+H)+
(FAB)

14

0.33

50% EtOAc
/ 50%
hexane

391

(M+H)+
(FAB)

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Table 3. 3-IsoquinolyI Ureas

Entry

R

mp
(°C)

HPLC
(min.)

TLC

TLC
Solvent
System

Mass Spec.
[Source]

15

0.60

50%
EtOAc /
50%
tiexane

278

(M+HJ+
(FAB)

16

0.52

50%
EtOAc /
50%
tiexane

(M+H)+
(FAB)

17

CI CI

0.75

50%
EtOAc /
50%
hexane

322

(M+H)+
(FAB)

18

0.57'

50%
EtOAc /
50%
hexane

314

(M+H)+
(FAB)

19

0.35

100%
EtOAc

355

(M+H)+
(FAB)

20

0.27

100%
EtOAc

357

(M+H)+
(FAB)

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Table 4. 3-Quinolyl Ureas

H H

Entry

mp
(°C)

HPLC
(min.)

TLC

TLC
Solvent
System

Mass Spec.
[Source]

21

0.25

60%
acetone /
40%
PH2C12

355

(M+H)+
(FAB)

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Table 5. 2-Methoxy-3-quinolyl Ureas

Entry

R

mp
(°C)

HPLC
(min.)

TLC

TLC
Solvent
System

Mass Spec.
[Source]

22

0.45

50%
EtOAc /
50%
tiexane

375 •
(M+H)+
(HPLC
ES-MS)

23

xro.

0.56

50%
EtOAc /
50%
hexane

385

(M+H)+
(FAB)

24

o

0.45

100%
EtOAc

399

(M+H)+
(FAB)

25

xro

207-
208

0.24

5% MeOH
' 95%
CH2C12

387

(M+H)+
(FAB)

26 ■

Me

126-
130

27

'AO

0.39

50%

acetone /

50%

CH2C12

403

(M+H)+
(FAB)

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Table 6.

3-QuinoIyI Ureas

Me'

Entry

mp
(°C)

HPLC
(min.)

TLC

TLC
Solvent
System

Mass Spec.
[Source]

2S

0.20

30%
MeOH /
70%
EtOAc

455

(M+H)+

(HPLC

ES-MS)

Table 7.

Additional Isoquinolyl Ureas

104

H H

0.30

1% Et3N/

99%

EtOAc

414

(M+H)+

(HPLC

ES-MS)

A2
C5

Table 8. 2-Methoxy-3-quinolyl Ureas with. Omega Carbonyls

■ H H J-.H
OMe

Entry

R

mp

(°C)

HPLC
(min.)

TLC

TLC
Solvent
System

Mass Spec.
[Source]

Synth.
Method

105

O

V-NH

-o-o w

213-
214

0.20

5%

MeOW

95%

CHC13

443
(FAB)

A13
C2c

106

O

y — nh

244-
245

A3 C2c

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107

o

_/ NH2

0.52

100%
EtOAc

430

(M+HH-
(FAB)

A2
C5

108

o

V-NH

-0-°-vv

0.55

100%
EtOAc

444

(M+H)+
(FAB)

A2
C5

109

0.30

100%
EtOAc

430

(M+H)+
(FAB)

A2
C5

110

\={ /={ Me

0.60

100%
EtOAc

444

(M+H)+
' (FAB)

A2
C5

111

O x Me

y — nh

(/ ^ — O — <\ /> — OMe

144-
146

A8
C5

112

-O-Qr

0

A3
C2c

BIOLOGICAL EXAMPLES

P38 Kinase Assay:

The in vitro inhibitory properties of compounds were determined using a p38
kinase inhibition assay. P38 activity was detected using an in vitro kinase assay run in
96-well microtiter plates. Recombinant human p38 (0.5 j-ig/mL) was mixed with substrate
(myelin basic protein, 5 ug/mL) in kinase buffer (25 mM Hepes, 20 mM MgCk and 150
mM NaCl) and' compound. One |j,Ci/well of 33 P-labeled ATP (10 pM) was added to a
final volume of 100 uL. The reaction was run at 32 °C for 30 min. and stopped with a 1M
HC1 solution. The amount of radioactivity incorporated into the substrate was determined
by trapping the labeled substrate onto negatively charged glass fiber filter paper using a

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1% phosphoric acid solution and read with a scintillation counter. Negative controls
include substrate plus ATP alone.

All compounds exemplified displayed p38 IC 50 s of between 1 nM and 10 uM.

5 LPS Induced TNFcc Production in Mice:

The in vivo inhibitory properties of selected compounds were determined using a
murine LPS induced TNFcc production in vivo model. BALB/c mice (Charles River
Breeding Laboratories; Kingston, NY) in groups of ten were treated with either vehicle or
compound by the route noted. After one hour, endotoxin (E. coli lipopolysaccharide

10 (LPS) 100 jLLg) was administered intraperitoneally (i.p.). After 90 min, animals were
euthanized by carbon dioxide asphyxiation and plasma was obtained from individual
animals by cardiac puncture into heparinized tubes. The samples were clarified by
centrifugation at 12,500 x g for 5 min at 4 °C. The supernatants were decanted to new
tubes, which were stored as needed at -20 °C. TNFa levels in sera were measured using

15 • a commercial murine TNF ELIS A kit (Genzyme).

The preceding examples can be repeated with similar success by substituting the
generically or specifically described reactants and/or operating conditions of this
invention for those used in the preceding examples.

20

From the foregoing discussion, one skilled in the art can easily ascertain the
essential characteristics of this invention and, without departing from the spirit and scope
thereof, can make various changes and modifications of the invention to adapt it to
various usages and conditions.

25

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WHAT IS CLAIMED IS:

1. A method of treating a disease mediated by p38 within a host, said method
comprising administering to said host a compound of Formula I:

A - D - B (I)

or a pharmaceutic ally acceptable salt thereof, wherein

D is -NH-C(0)-NH-,

A is a substituted or unsubstituted pyridyl, quinolinyl or isoquinolinyl group,
B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of
up to 50 carbon atoms with a cyclic structure bound directly to D, containing. at least 5
cyclic members with 0-4 members of groups consisting of nitrogen, oxygen and sulfur,

wherein the substituents for A are selected from the group consisting of halogen,
up to per-halo, and Wn, where n is 0-3 and each W is independently selected from the
group consisting of

Ci-io alkyl, Ci-io alkoxy, C3-10 cycloalkyl having at least a five cyclic members
and 0-3 heteroatoms selected from N, S and O; C2-10 alkenyl, C1-10 alkenoyl, C6-C14 aryl,
C7-C24 alkaryl, C7-C24 aralkyl, C3-C12 heteroaryl having at least 5 cyclic members and 1-3
heteroatoms selected from O, N and S, C4-C24 alkheteroaryl having at least 5 cyclic
members and 1-3 heteroatoms selected from O, N and S;

substituted C1-10 alkyl, substituted Ci-io alkoxy, substituted C3-10 cycloalkyl
having at least 5 cyclic members and 0-3 heteroatoms selected from N, S and O;
substituted C2-10 alkenyl, substituted C M o alkenoyl, substituted C6-C14 aryl, substituted
C7-C24 alkaryl, substituted C7-C24 aralkyl, substituted C3-C12 heteroaryl having at least 5
members and 1-3 heteratoms selected from O, N and S, substituted C4-C24 alkheteroaryl
having at least 5 members and 1 -3 heteroatoms selected from O, N and S,

-CN, -C0 2 R 7 , -C(0)NR 7 R 7 ', -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 ', -
NR 7 C(0)OR 7 ', -NR 7 C(0)R 7 ', with each R 7 and R 7 ' independently selected from

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hydrogen, Ci_i 0 alkyl, Clio alkoxy, C 2 -io alkenyl, Clio alkenoyl, up to per halosubstituted
Ci-io alkyl, up to per halosubstituted Ci-io alkoxy, up to per halosubstituted C2-10 alkenyl
and up to per halosubstituted Cm 0 alkenoyl, C3-C10 cycloalkyl having at least 5 cyclic
members and 0-3 heteroatoms selected from O, S and N, C6-C14 aryl, C3-C10 hetaryl
having at least 6 cyclic members and 0-3 heteroatoms selected from O, S and N, up to per
halo substituted C3-C10 cycloalkyl having at least 5 cyclic members and 0-3 heteroatoms
selected from O, S and N, up to per halo substituted Cs-Cu aryl and up to per halo
substituted C3-C10 hetaryl having at least 6 cyclic members and 0-3 heteroatoms selected
from O, S and N,

where W is a substituted group, it is substituted by halogen, up to per halo, or by
one or more substituents independently selected from the group consisting of -CN, -
C0 2 R 7 , -C(0)NR 7 R 7 ', -C(0)-R 7 , -N0 2 , -OR 7 , -SR 7 , -NR 7 R 7 ', -NR 7 C(0)OR 7 ', and -
NR 7 C(0)R 7 ', wherein R 7 and R 7 ' are independently as defined above;

wherein the sxibstituents for B are selected from the group consisting of halogen,
up to per-halo, and J n , where n is 0-3 and each J is independently selected from the group
consisting of -CN, -C0 2 R 7 , -C(0)NR 7 R 7 ', -C(0)-R 7 , -NO2. -OR 7 , -SR 7 , -NR 7 R 7 ', -
NR 7 C(0)OR 7 ', -NR 7 C(0)R 7 ', with each R 7 and R 7 ' independently as denned for W
above, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having at least five cyclic members and
0-3 heteroatoms, C2-10 alkenyl, Cmo alkenoyl, C 6 .u aryl, C3-12 hetaryl having at least a
five cyclic members and 1-3 heteroatoms selected from N, S and O, C7-24 aralkyl, C 7 . 2 4
alkaryl, C4-C23 alkyheteroaryl having at least six members and 1-3 heteroatoms sleeted
from O, N and S, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C3-10
cycloalkyl having at least a five-members and 0-3 heteroatoms selected from N, S and O,
substituted C 2 -io alkenyl, substituted Ci- 10 alkenoyl, substituted C 6 - C 14 aryl, substituted
C3-12 hetaryl having at least five cyclic members and 1-3 heteroatoms selected from N, S
and O, substituted C7.24 alkaryl, substituted C 7 -C 2 4 aralkyl and substituted C 4 -C 23
alkyheteroaryl having at least six members and 1-3 heteroatoms sleeted from O, N and S,
and -Q-Ar,

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wherein Q is a single bond, -O-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(O)-, -CH(OH)-, -
(CH 2 ) ra O-, -(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX\ -CX a 2 -, -S-(CH 2 ) ra - and -
N(R 7 )(CH 2 ) m -, wherein m= 1-3, andX a is halogen; and

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from
the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by
halogen, up to per-halo, and optionally substituted by Z nl , wherein nl is 0 to 3 and each Z
is independently selected from the group consisting of -CN, -C0 2 R 7 , -COR 7 , -
C(0)NR 7 R 7 ', -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 ', -NR 7 C(0)R 7 ', and -NR 7 C(0)OR 7 , with R 7 and
R 7 ' as defined above for W, Ci-io alkyl, Ci-io alkoxy, C2-10 alkenyl and Ci-i 0 alkenoyl,
halo substituted C1.10 alkyl up to per halo, halo substituted Cmo alkoxy up to per halo,
halosubstituted C 2 -io alkenyl \ip to per halo and halo substituted C1-10 alkenoyl up to per
halo, and

where J is a substituted group, it is substituted by halogen, up to per halo, or by
one or more substitutents independently selected from the group consisting of -CN, -
C0 2 R 7 , -COR 7 , -C(0)NR 7 R 7 ', -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 ', -NR 7 C(0)R 7 ', and -
NR 7 C(0)OR 7 ', with R 7 and R 7 ' as defined above for W.

2. A method of claim 1 wherein B of formula I is

a substituted or unsubstituted bridged cyclic structure of up to 30 carbon atoms,
a substituted or unsubstituted 6 member cyclic aryl moiety or a 5-6 member cyclic
hetaryl moiety or

a substituted or unsubstituted fused ring structure of from 2-3 fused aryl rings, • •
hetaryl rings or both aryl and hetaryl rings.

3. A method as in claim 2 wherein B of formula I is a bridged cyclic structure of
the formula -L-(ML l ) q , where L is a 5 or 6 membered cyclic structure bound directly to
D, L 1 comprises a substituted cyclic moiety having a least 5 members, M is a bridging
group having at least one atom, q is an integer of from 1-3, and each cyclic structure of L
and L 1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur,
wherein L 1 is substituted by at least one substituent selected from the group consisting of

a)
b)

c)

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-S0 2 R a , -S0 2 NR a R b , -C(0)R a , -C(0)NR a R b and -C(NR a )R b , wherein R a and R b are
independently hydrogen or a carbon based moiety.

4. A method of claim 3 wherein M in the formula — L-fML^q, is selected from the
group consisting of-O-, -S-, -N(R 7 )-, J (CH 2 ) m -, -C(O)-, -CH(OH)-, -( CH 2 ) ra O-, .

-( CH 2 ) m S-, -( CH 2 ) m N(R 7 )-, -0(CH 2 ) m -; -CHX\ -CX a 2 -, -S-(CH 2 ) ra -, -CR a R b -, and
— N(R 7 )(CH2) m -, where m=l-3, X a is halogen, q is 1, and R a and R b are as defined in claim
3, and R 7 is selected from the group consisting of hydrogen, Ci-io alkyl, Ci. 10 alkoxy, C 2 .
io alkenyl, Ci-io alkenoyl, up to per halosubstituted Cmo alkyl, up to per halosubstituted
Ci-io alkoxy, up to per halosubstituted C 2 -io alkenyl and up to per halosiibstituted Ci-io
alkenoyl.

5. A method of claim 4 wherein L in the formula -L-(ML l ) q for B is a
substituted 6 member cyclic aryl moiety, a substituted 5 or 6 member heterocyclic
moiety, an unsubstituted 6 member cyclic aryl moiety, or an unsubstituted 5 or 6 member
heterocyclic moiety, and L 1 in the formula -L-(ML') q for B, is a substituted aryl moiety
having at least 6 cyclic members, an unsubstituted aryl moiety having at least 6 cyclic
members, a substituted hetaryl moiety having at least 6 cyclic members or an
unsubstituted hetaryl moiety having at least 6 cyclic members, said heterocyclic and
hetaryl moieties having 1 to 4 members selected from the group of hetero atoms
consisting of nitrogen, oxygen and sulfur with the balance of the hetaryl and heterocyclic
moiety being carbon. ...

6. A method of claim 1 wherein B is phenyl, substituted phenyl, pyridinyl,
substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, quinolinyl, substituted
quinolinyl, isoquinolinyl, substituted isoquinolinyl or of the formula -L(ML l ) q , wherein
L 1 and L in formula— L(ML l ) q for B, are each independently selected from the group
consisting of thiophene, substituted thiophene, phenyl, substituted phenyl, napthyl,
substituted napthyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl,
quinolinyl substituted quinolinyl, isoquinolinyl and substituted isoquinolinyl.

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7. A method of claim 6 wherein B is a substituted group, substituted by -CN,
halogen up to per halo, Ci-io alkyl, Cmo alkoxy,-OH, up to per halo substituted Cmo
alkyl, up to per halo substituted Cmo alkoxy, -OR 7 , -SR 7 , -NR 7 R 7 ' -C0 2 R 7 , -
C(0)NR 7 R 7 ', -C(0)R 7 or -NO2, wherein each R 7 and R 7 ' are independently selected from
hydrogen, Cmo alkyl, Cmo alkoxy, C2-10 alkenyl, Cmo alkenoyl, up to per halosubstituted
Cmo alkyl, up to per halosubstituted Cmo alkoxy, up to per halosubstituted C2-10 alkenyl
and up to per halosubstituted Cmo alkenoyl.

8. A compound of claim 6 wherein M in the formula — L-^ML 1 ) for B is — 0-, -
CH 2 -, -S-, -NH-, -C(O)-, -0-CH 2 -or-CH 2 -0-.

9. A method of claim 6, wherein A has 1-3 substituents selected from the group
.consisting of Cmo alkyl, up to per halo substituted Cmo alkyl, -CN, -OH, halogen, Cmo
alkoxy, up to per halo substituted Cmo alkoxy and C3-10 heterocyclic moieties having at
least 5 cyclic members and 1 to 2 heteroatoms selected from the group of consisting of
nitrogen, oxygen and sulfur.

10. A method of claim 6 wherein L 1 is substituted 1 to 3 times by one or more
substituents selected from the group consisting of -CN, halogen up to per halo, Cmo
alkyl, Cmo alkoxy,-OH, up to per halo substituted Cmo alkyl, up to per halo substituted
Cmo alkoxy, -OR 7 , -SR 7 , -NR 7 R 7 ' -C0 2 R 7 , -C(0)NR 7 R 7 ', -C(0)R 7 or -NO2, wherein
each R 7 and R 7 ' is independently selected from hydrogen, Cmo alkyl, Cmo alkoxy, C2-10
alkenyl, Cmo alkenoyl, up to per halosubstituted Cmo alkyl, up to per halosubstituted C\.
10 alkoxy, up to per halosubstituted C2-10 alkenyl and up to per halosubstituted Cmo
alkenoyl.

11. A method of claim 1 wherein a pharmaceutically acceptable salt of a
compound of formula I is administered which is selected from the group consisting of

a) basic salts of organic acids and inorganic acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric

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acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-
toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene
sulfonic acid, acetic acid, trifluoro acetic acid, malic acid, tartaric acid, citric
acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic
acid, salicylic acid, phenylacetic acid, and mandelic acid; and
b) acid salts of organic and inorganic bases containing cations selected from the
group consisting of alkaline cations, alkaline earth cations, the ammonium
cation, aliphatic substituted ammonium cations and aromatic substittued
ammonium cations.

12. A method as in claim 1 for the treatment of a disease other than cancer.

13. A method as in claim 1 wherein the condition within a host treated by
administering a compound of formula I is rheumatoid arthritis, osteoarthritis, septic
arthritis, tumor metastasis, periodontal disease, corneal ulceration, proteinuria, coronary
thrombosis from atherosclerotic plaque, aneurysmal aortic, birth control, dystrophobic
epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury,
osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating
disease of the nervous system.

14. A method as in claim 1 wherein the condition within a host treated by
administering a compound of formula I is rheumatic, fever,, .bone resorption,
postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic
shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory
bowel disease (Crohn's disease and ulcerative colitis), Jarisch-Herxheimer reaction,
asthma, adult respiratory distress syndrome, acute pulmonary fibrotic disease, pulmonary
sarcoidosis, allergic respiratory disease, silicosis, coal worker's pneumoconiosis, alveolar
injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis,
malaria (Plasmoditvm falciparum malaria and cerebral malaria), non-insulin-dependent
diabetes mellitus (TS1TDDM), congestive heart failure, damage following heart disease,
atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis

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(demyelation and oligodendrocyte loss in multiple sclerosis), advanced cancer,
lymphoid malignancy, pancreatitis, impaired wound healing in infection, inflammation
and cancer, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis,
bowel necrosis, psoriasis, radiation injury/ toxicity following administration of
monoclonal antibodies, host-versus-graft reaction (ischemia reperfusion injury and
allograft rejections of kidney, liver, heart, and skin), lung allograft rejection (obliterative
bronchitis) or complications due to total hip replacement.

15. A method as in claim 1 wherein the condition within a host treated by
administering a compound of formula I is an an infectious disease selected from the
group consisting of tuberculosis, Helicobacter pylori infection during peptic ulcer
disease, Chaga's disease resulting from Trypanosoma cruzi infection, effects of Shiga-
like toxin resulting from E. coli infection, effects of enterotoxin A resulting from
Staphylococcus infection, meningococcal infection, and infections from Borrelia
burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus,' Theiler's
encephalomyelitis virus, and the human iminunodeficiency virus (HIV).

16. A method as in claim 3 wherein:
R a and Rb are,

a) independently hydrogen,

a carbon based moiety selected from the group consisting of Ci-Cio alkyl, Ci-Cio
alkoxy, C3-10 cycloalkyl having 0-3 hetero atoms selected from N, S and O, C2-10 alkenyl,
Ci-10 alkenoyl, C6-u aryl, C3-12 hetaryl having 1-3 heteroatoms selected from O, N and S,
C7-24 aralkyl, C7-C24 alkaryl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted
C3-10 cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted aryl,
substituted C3.12 hetaryl having 1-3 heteroatoms selected from N. S and O, substituted C7.
24 aralkyl, substituted C7.24 alkaryl, where R a and R b are a substituted group, they are
sxibstituted by halogen up to per halo, hydroxy, d_io alkyl, C3.12 cycloalkyl having 0-3
heteroatoms selected from O, S andN, C3.12 hetaryl having 1-3 heteroatoms selected
from N, S and O, C1-10 alkoxy, Ce-u aryl, C1-6 halo substituted alkyl up to per halo alkyl,
C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having

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0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-
C12 hetaryl up to per halo heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl,
halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(0)R g ; or

-OSi(Rf)3 where Rf is hydrogen, Ci-io alkyl, C1-10 alkyl, Cmo alkoxy, C3-C10
cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-12 aryl, C3-C12 hetaryl
having 1-3 heteroatoms selected from O, S andN, C7.24 aralkyl, substituted Cuo alkyl,
substituted C1-C10 alkoxy, substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected
from O, S and N, substituted C3-Q2 heteraryl having 1-3 heteroatoms selected from O, S,
and N, substituted C6-12 a *ylr and substituted C7-24 alkaryl, where R f is a substituted group
it is substituted halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3
heteroatoms selected from O, S andN, C3-12 hetaryl having 1-3 heteroatoms selected
fromN, S and O, Ci-io alkoxy, Ce-i2 aryl, C y .-C24 alkaryl, C7-C24 aralkyl, Ci-e halo
substituted alkyl up to per halo alkyl, C&-C\2 halo substituted aryl up to per halo aryl, C3-
C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to
per halo cycloalkyl, halo substituted C3-Q2 hetaryl up to per halo heteraryl, halo
substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per
halo alkaryl, and -C(0)R g ,

or

b) R a and Rb together form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure
of 1-3 heteroatoms selected from N, S and O with substituents selected from the group
consisting of halogen up to per halo, hydroxy, Cmo alkyl,,, C3.U cycloalkyl having 0-3
heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected
from N, S and O, d-io alkoxy, Ce-u aryl, C7-C24 alkaryl, C 7 -C 2 4 aralkyl, halo substituted
C1-6 alkyl up to per halo alkyl, halo substituted C6-C12 aryl up to per halo aryl, halo
substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per
halo cycloalkyl, halo substituted C3-Q2 hetaryl up to per halo heteraryl, halo substituted
C7-C12 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo
alkaryl, and -C(0)R g ,

or

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c) one of R a or Rb is -C(O)-, a C1-C5 divalent alkylene group or a substituted
C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at
least 5 members,

wherein the substituents of the substituted C1-C5 divalent alkylene group are selected
from the group consisting of halogen, hydroxy, C1-10 alkyl, C3.12 cycloalkyl having 0-3
heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected
from N, S and O, C1-10 alkoxy, C6-12 aryl, C7-C24 alkaryl, C7-C24 aralkyl, Ci-6 halo
substituted alkyl up to per halo alkyl, C6-C 12 halo substituted aryl up to per halo aryl, C3-
C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to
per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteraryl, halo
substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per
halo alkaryl, and -C(0)R g ,

where R g is C M0 alkyl; -CN, -C0 2 Rd, -ORd, -SRd,. -NO2, -C(O) Re, -NRaRe, -NRd
C(0)ORe and -NRd C(0)Re, and Rj and Re are independently selected from the group
consisting of hydrogen, Cmo, alkyl, C1-10 alkoxy, C3.10 cycloalkyl having 0-3 heteroatoms
selected from O, N and S, C6-12 aryl, C3-C12 hetaryl with 1-3 heteroatoms selected from
O, N and S and C7-C24 aralkyl, C7-C24 alkaryl, up to per halo substituted C1-C10 alkyl, up
to per halo substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and
S, up to per halo substituted C6-C14 aryl, up to per halo substituted C3-C12 hetaryl having
1-3 heteroatoms selected from O, N, and S, halo substituted C7-C24 alkaryl up to per halo
alkaryl, and up to per halo substituted C7-C24 aralkyl.

17. A method as in claim 4, wherein said substituted cyclic moiety L 1 is
phenyl, pyridyl or pyrimidinyl.

18. A method of claim 3 wherein L 1 is substituted by -C(0)NR a R b or -
S0 2 NR a R b .

19. A method for the treatment of a disease mediated by p38 kinase other than
cancer which comprises administering a compound selected from the group consisting of

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Af-(2-Methoxy-3-qiiinolyl)-Af'-(4-[^

iV-(2-Methoxy-3-quinolyl)-A r '-(4-[2-(A r -methylcarbamoyl)-4-pyridy

A f -(2-Methoxy-3-quinolyl)-A^'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea

iV-(2-Methoxy-3-qumolyl)-iV'-(3-[2-(A r -methylcarbamoyl)-4-pyridyloxy

A^-(2-Methoxy-3-qixinolyl)-A'''-(3-(2-carbamoyl)-4-pyridyloxy)phenyl)iirea

A^(2-Memoxy-3-qumolyl)-AT-(4-[3-(^

7V-(2-Methoxy-3-quinolyl)-iV'-(4-[4-methoxy-3-(N-
methylcarbamoyl)phenoxy]phenyl)urea

A^-(34soquinolyl)-A^'-(4-[2-(iV-methylcarbamoyl)-4-pyridyloxy]phenyl)urea
and pharmaceutically acceptable salts thereof.

20. A compound of the following formula

A'-D-B' (I)

or a pharmaceutically acceptable salt thereof, wherein

D is -NH-C(0)-NH-,

A' is selected from the group consisting of substituted t-butylpyridinyl,
unsubstituted t-butylpyridiyL substituted (trifluoromethyl)pyridyl, unsubstituted
(trifluoromethyl)pyridyl, substituted isopropylpyridyl, unsubstituted isopropylpyridyl,
substituted (2-methyl-2-butyl)pyridyl, unsubstituted (2-methyl-2-butyl)pyridyl,
substituted (3-ethyl-3-pentyl)pyridyl, unsubstituted (3-ethyl-3-pentyl)pyridyl, substituted
isoquinolinyl, unsubstituted isoquinolinyl and unsubstituted quinolinyl,

B' is

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a) a substituted or unsubstituted aryl ring having 6 cyclic members,

b) a substituted or unsubstituted heterocyclic, ring having at least 5 cyclic
members and 1-3 heteroatoms sleeted from O, S andN,

c) a substituted or imsubstituted fused ring structure of from 2-3 fused aryl rings,
hetaryl rings or both aryl or hetaryl rings of up to 30 carbon atoms or

where A' is substituted or unsubsituted t-butylpyridyl (trifiuoromethyl)pyridyl,
isopropylpyridyl, (2-methyl-2-butyl)pyridyl or (3-ethyl-3-pentyl)pyridyl, or

where A' is substituted isoquinolinyl, imsubstituted isoquinolinyl or unsubstituted
quinolinyl.

21. A pharmaceutical composition comprising a compound of claim 20 and a
physiologically acceptable carrier.

22. A compound of claim 20, wherein A' has 1-3 substituents selected from the
group consisting of Ci-io alkyl, up to per halo substituted Ci-io alkyl, -CN, -OH, halogen,
Ci-io alkoxy, up to per halo substituted Ci_io alkoxy and C3-10 heterocyclic moieties
having at least a five cyclic members and 1 to 2 heteroatoms selected from the group of
consisting of nitrogen, oxygen and sulfur.

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23. A compound of claim 20 wherein B' is a substituted group substituted by -
CN, halogen, Ci-io alkyl, C W o alkoxy,-OH, up to per halo substituted Ci-io alkyl, up to
per halo substituted Clio alkoxy -OR 7 , -SR 7 , -NR 7 R 7 ', -NR 7 C(0)OR 7 ', -NR 7 C(0)R 7 ' or -
NO2, wherein each R 7 and R 7 ' is independently selected from hydrogen, Clio alkyl, Cmo
alkoxy, C2-10 alkenyl, Ci-io alkenoyl, up to per halosubstituted Ci-io alkyl, up to per
halosubstituted d.10 alkoxy, up to per halosubstituted C2-10 alkenyl and up to per
halosubstituted Ci-io alkenoyl.

24. A compound of claim 20 wherein B' is thiophene, substituted thiophene,
substituted phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl,
substituted pyrimidinyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted
isoquinolinyl, napthyl or substituted napthyl.

25. A compound of claim 20 which is a pharmaceutically acceptable salt of a
compound of formula I' selected from the group consisting of

a) basic salts of organic acids and inorganic acids selected from the group
consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, trifluoro sulfonic acid, benzenesulfonic acid, p-
toluene sulfonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene
sulfonic acid, acetic acid, trifhioroacetic acid, malic acid, tartaric acid, citric
acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic
acid, salicylic acid, phenyiacetic acid, and mandelic acid; and

b) acid salts of organic and inorganic bases containing cations selected from the
group consistng of alkaline cations, alkaline earth cations, the ammonium
cation, aliphatic substituted ammonium cations and aromatic substituted
ammonium cations.

26. A compound selected from the group consisting of

N-(4-tert-butylpyridinyl)-N'-(4-methylphenyl) urea
N-(4-tert-butylpyridinyl)-N'-(4-flviorophenyl) urea

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N-(4-tert-hutylpyridinyl)-N'-(2,3-dichlorophenyl) urea
N-(4-tert-butylpyridinyl)-N' -(1 -naphthyl) urea
N-(4-tert-butylpyridmyl)-N'-(4-)4-methoxyphenoxy)phenyl) urea
N-(2-)(54rifluoromethyl)pyridinloxy-N'-(4-)4-pyridylmethyl)phenyl) urea
N-(2-)(54rifiuoromethyl)pyridinloxy-N , -(3-)4-pyridylthio)phenyl) urea
N-(3-isoquinolyl)-N'-(4-methylphenyl) urea
N-(3-isoquinolyl)-N'-(4-fluorophenyl) urea
N-(3-isoquinolyl)-N'-(2 3 3-dich.loroplienyl) urea
N-(3-isoquinolyl) : N'-(l-naphthyl) urea
N-(3 -iso quinolyl)-N' -(4-)4-pyridinylmethyl)phenyl) urea
N-(3 -quinolyl)-N' - (4-)4-pyridinylmethyl)phenyl) urea

27. A method of treating a disease mediated by p38 within a host, said method
comprising administering a compound of claim 20.

28. A pharmaceutical composition for the treatment of a disease within a host
mediated by p38 comprising an amount of a compound of Formula I effective to inhibit
p38 mediated events,

A - D - B (I)

or a pharmaceutically acceptable salt thereof, in an amount effective to treat a disease
mediated by p3 8 and a physiologically acceptable carrier:

wherein

D is -NH-C(0)-NH-,

A is as defined in claim 1
B is as defined in claim 1

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29. A pharmaceutical composition as in claim 28 wherein B of formula I is

a) a substituted or unsubstituted bridged cyclic structure of up to 30 carbon
atoms,

b) a substituted or unsubstituted 6 member cyclic aryl moiety or a 5-6 member
cyclic hetaryl moiety or

c) a substituted or unsubstituted fused ring structure of from 2-3 fused aryl rings,
hetaryl rings or both aryl and hetaryl rings.

30. A pharmaceutical composition as in claim 29 wherein B of formula I is a
bridged cyclic structure of the formula -L^ML 1 ),, where L is a 5 or 6 membered cyclic
structure bound directrly to D, L 1 comprises a substituted cyclic moiety having a least 5
members, M is a bridging group having at least one atom, q is an integer of from 1-3, and
each cyclic structure of L and L 1 contains 0-4 members of the group consisting of
nitrogen, oxygen and sulfur, wherein L 1 is substituted by at least one substituent selected
from the group consisting of -SO2R*, -C(0)R x , and -C(NR y )R z wherein R y is hydrogen
or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms
selected from N, S and O and optionally halosubstituted, up to per halo,

R z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally
containing heteroatoms selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally
contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R x is R z or NR a Rb where R a and Rb are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing
heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy
and carbon based substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O and are optionally substituted by halogen, or

-OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon
atoms optionally containing heteroatoms selected from N, S and O and optionally
substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms,

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which optionally contain heteroatoms selected from N, S and O and are optionally
substituted by halogen; or

b) R a and Rb together form a 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O, or a substituted 5-7 member
heterocyclic structure of 1-3 heteroatoms selected from N, S and O
substituted by halogen, hydroxy or carbon based substituents of up to 24
carbon atoms, which optionally contain heteroatoms selected from N, S
and O and are optionally substituted by halogen; or

c) one of R a or Rb is -C(O)-, a C1-C5 divalent alkylene group or a substituted
C1-C5 divalent alkylene group bound to the moiety L to form a cyclic
structure with at least 5 members, wherein the substituents of the
substituted C1-C5 divalent alkylene group are selected from the group
consisting of halogen, hydroxy, and carbon based substituents of up to 24
carbon atoms, which optionally contain heteroatoms selected from N, S
and O and are optionally substituted by halogen.

31. A pharmaceutical composition as in claim 30 wherein the cyclic structures
of B and L bound directly to D are not substituted in the ortho position by —OH or a
moiety having an ionizable hydrogen and a pKa of 10 or less.

32. A pharmaceutical composition as in claim 28 wherein B of Formula I is a
substituted or unsubstituted six member aryl moiety or at least a five member heterocylic
moiety, said heterocyclic' moiety having 1 to 4 members selected from the group of
hetaryl atoms consisting of nitrogen, oxygen and sulphur with the balance of the
heterocylic moiety being carbon.

33. A pharmaceutical composition as in claim 30 wherein B of Formula I is an
unsubstituted phenyl group, an imsubstituted pyridyl group, an unsubstituted pyrimidinyl
group, a phenyl group substituted by a substituent selected from the group consisting of
halogen and Wn wherein W and n are as defined in claim 30, a pyrimidinyl group
substituted by a substitutent selected from halogen and Wn, wherein W and n are as
defined in Claim 30, or a pyridyl group substituted by a substituent selected from the
group consisting of halogen and Wn wherein W and n are as defined in claim 30.

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34. A pharmaceutical composition as in claim 30, wherein L, the 5 or 6
member cyclic structure bound directly to D, is a substituted or unsubstituted 6 member
heteroaryl moiety, wherein said heteroaryl moiety has 1 to 4 members selected from the
group of heteroatoms consisting of nitrogen, oxygen and sulphur with the balance of said
hetaryl moiety being carbon, wherein the one or more substituents are selected from the
group consisting of halogen and Wn, wherein W and n are as defined in claim 30.

35. A pharmaceutical composition as in claim 30, wherein L, the 5 or 6
member cyclic structure bound directly to D, is a substituted phenyl, substituted
thiophene, unsubstituted thiophene, substituted napthyl, unsubstituted napthyl,
unsubstituted phenyl, substituted pyridyl, unsubstituted pyridyl group, unsubstituted
pryimidinyl or substituted prymidinyl.

36. A pharmaceutical composition as in claim 30, wherein said substituted cyclic
moiety L 1 is phenyl, pyridyl or pyrimidinyl and M is one or more bridging groups
selected from the group consisting of -0-, -S-, -N(R 7 )-, -(CH 2 ) m -, -C(0)-, -CH(OH)-, - .
(CH 2 ) m O-, -(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m - CHX\ -CX a 2 -, -S-(CH 2 ) m - and -
N(R 7 )(CH 2 ) m -, where m= 1-3, X a is halogen and R 7 is hydrogen or a carbon based moiety
of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O
and optionally substituted by halogen up to per halo.

37. A pharmaceutical composition as in claim 30 wherein L 1 is substituted by
-C(0)R x .

38. A pharmaceutical composition as in claim 30 wherein L 1 is substituted by
-C(0)R x or -S0 2 R x , wherein R x is NRRb.

39. A pharmaceutical composition for the treatment of a disease within a host
mediated by p38 comprising a compound selected from the group consisting of

A/-(2-Methoxy-3-quinolyl)-iV'-(4-[3-(iV'-methylcarbamoyl)phenoxy]phenyl)urea
A^-(2-Medioxy-3-quinolyl)-iV'-(4-[2-(iV-methylcarbamoyl)-4-pyridyloxy]phenyl)urea

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7V"-(2-Methoxy-3-quinolyl)-iV'-(4-(2-carbamoyl-4-pyridyloxy)phenyl)urea

A r -(2-Methoxy-3-q\iinolyl)-iV'<3-[2-(iV-methylcarbamoyl)-4-pyridyloxy]phen^

iV-(2-Methoxy-3-qmnolyl)-AA'-(3-(2-carbamoyl)-4-pyridyloxy)phenyl)-urea

jV"-(2-Methoxy-3-quinolyl)^H4^3-(A r -iso

A r -(2-Methoxy-3-quinolyl)-A^'-(4-[4-methoxy-3-(N-
methylcarbamoyl)phenoxy]phenyl)urea

A^(3-Isoquinolyl)-N 1 -(4-[2-(N-methylcarbamoyl)-4-pyridyIoxy]phenyl)iirea
and pharmaceutically acceptable salts thereof.

92

INTERNATIONAL SEARCH REPORT

In ional Application No

PCT/US 02/12064

A. CLASSIFICATION OF SUBJECT MATTER

IPC 7 C07D213/75 C07D217/22 C07D401/12 C07D215/38 C07D403/12
A61K31/44 A61K31/47 A61P29/00

According lo International Patent Clas sification (IPC) orto both national classification and IPC

B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

IPC 7 C07D

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

EPO-Internal , WPI Data, PAJ, BEILSTEIN Data

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category ° Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

MUIJLWIJK-KOEZEN, O.E. ET. AL . :

"Isoquinol Ine and Quinazoline Urea

Analogues as Antagonists for the Human

Adenosine A3 Receptor."

JOURNAL OF MEDICINAL CHEMISTRY,

vol. 43, no. 11, 2000, pages 2227-38,

XP002147879

Table 1, compounds 8a, 8b, 8d

_/--

20,21,
25,28,
29,32,33

Further documents are listed in the continuation of box C.

Patent family members are listed in annex.

" Special categories of cited documents :

"A" document defining the general state of the art which is not
considered to be of particular rele/ance

"E" earlier document but published on or after the international
filing date

"L" document which may throw doubts on priority claim(s)or
which is cited to establish the publication date of another
citation or other special reason (as specified)

"O* document referring to an oral disclosure, use, exhibition or
other means

"P" document published prior to the international filing date but
later than the priority dale claimed

'T - later document published after the international filing date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention

"X" document of particular relevance; the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is taken alone

"Y" document of particular relevance; the claimed invention

cannot be considered to involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.

document member of the same patent family

Date of the actual completion of the international search

13 September 2002

Date of mailing of the international search report

20/09/2002

Name and mailing address of the ISA

European Patent Office, P.B. 5818 Patentlaan 2
NL - 2280 HV Rijswp
Tel. (+31-70) 340-2040. Tx. 31 651 epo nl.
Fax: (+31-70) 340-3016

Authorized officer

Helps, I

Foim PCT/1SA/210 (second sheet) (July 1992)

page 1 of 2

INTERNATIONAL SEARCH REPORT

Ir-^.-.^tional Application No

PCT/US 02/12064

C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT

Category °

Citation of document, with indication.where appropriate, of trie relevant passages

Relevant to claim No.

A

f ARI TNG R Ul FT Al

9D ?1

" l-( 3-Cyanobenzyl p i peri di n-4-yl )-5-methyl -

4-pnenyl 1 , 3-dihydroimidazol-2-one : A

Oc IctU 1 Vtf niyll ATT 1 I II Lj rtllU ay U 1] 1 i> b TUl U I lu

nUlllall U Up dill 1 1 It: 1/4 l\cL.tf|J LUl WILlI LALc ] 1 fcrll L

Selectivity over Ion Channels"

JOURNAL OF MEDICINAL CHEMISTRY,

\/n1 &9 nn 1 A 1 QQQ nanpc 970^—1 P\
vui . H-t., nu. J.yi7i7 , payt?i> l/ud j.o 3

Tab! p 7 romnminfi 7

X

US 4 279 639 A ( 0KAM0T0 ET. AL.)

20,22

21 July 1981 (1981-07-21)

tr A amp 1 co Zj O

y

1 9 ft 7

1 Julv 1999 f 1999-07-01")

X U U 1 jr J. Z7 Z* ZS \ 1. Zs Z/ Z? \J I \J A. J

9 1 1 -1 R

28,29,32

page 4, line 28 -page 7, line 17; claims

V

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A

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I

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page 6, line 29 -page 8, line 9

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H

UUrlHo , U . CI. ML . . I r ileliy I 0 pyr dZU I j I

j.— oy

ui cdo . ruuciiu alio oc I cut t vc poo k i iiaoc

I nh i bi tops . "

BIOORGANIc'AND MEDICINAL CHEMISTRY

LETTERS,

vui . iu , lUuu 5 pages £UOi ArvjUM-^njooUr

A

W0 99 32111 A (BAYER CORPORATION)

1-39

1 July 1999 (1999-07-01)

page 5, line 15 -page 6, line 9; claims;

exampl es

P,Y

W0 01 36403 A (BOEHRINGER INGELHEIM

1-39

PHARMACEUTICALS INC.)

25 May 2001 (2001-05-25)

claims; examples

Form PCT/ISA/210 (continuation of second sheet) (July 1992)

page 2 of 2

INTERNATIONAL SEARCH REPORT

International application-No.
PCT/US 02/12064

Box i Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)

This International Search Report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
1. [Y] Claims Nos.:

because they relate to subject matter not required to be searched by this Authority, namely:

Although claims 1-19 and 27 are directed to a method of treatment of the
human/animal body, the search has been carried out and based on the alleged
effects of the compound/composition.

□

Claims Nos.:

because they relate to parts of the international Application that do not comply with the prescribed requirements to such
an extent that no meaningful International Search can be carried out, specifically:

3. \^\ Claims Nos.:

because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)

This International Searching Authority found multiple indentions in this international application, as follows:

1 . As all required additional search fees were timely paid by the applicant, this International Search Report covers all
' ' searchable claims.

2. | | As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment

of any additional fee.

3. I I As only some of the required additional search fees were timely paid by the applicant, this International Search Report
' — ' covers only those claims for which fees were paid, specifically claims Nos.:

4. | I No required additional search fees were timely paid by the applicant. Consequently, this International Search Report is
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

Remark on Protest j The additional search fees were accompanied by the applicant's protest.

j No protest accompanied the payment of additional search fees.

Form PCT/ISA/210 (continuation of first sheet (1)) (July 1998)

INTERNATIONAL SEARCH REPORT

Information on patent family members

In ional Application No

PCT/US 02/12064

Patent document
cited in search report

Publication
date

Patent family
member(s)

Publication
date

US 4279639

21-07-1981

AU
AU
BR
CA
EP
ZA

536653 B2
5244479 A
7907120 A
1134832 Al
0010770 Al
7905821 A

W0 9932463

01-07-1999

AU 1939999 A

CA 2315715 Al

DE 1042305 Tl

EP 1042305 Al

ES 2154252 Tl

JP 2001526276 T

W0 9932463 Al

17-05-1984
08-05-1980
05-08-1980
02-11-1982
14-05-1980
26-11-1980

12-07-1999
01-07-1999
19-04-2001
11-10-2000
01-04-2001
18-12-2001
01-07-1999

WO 0041698 A 20-07-2000 AU 2725000 A 01-08-2000

EP 1158985 Al 05-12-2001

WO 0041698 Al 20-07-2000

US 2002065296 Al 30-05-2002

WO 9932111 A 01-07-1999

AU

739642

B2

18-

-10-

-2001

AU

1997199

A

12-

-07-

-1999

CA

2315720

Al

01-

-07-

-1999

DE

1041982

Tl

07-

-06-

-2001

EP

1041982

Al

11-

10-

-2000

ES

2154253

Tl

01-

-04-

-2001

JP

2001526223

T

18-

-12-

-2001

WO

9932111

Al

01-

-07-

-1999

W0 0136403 A 25-05-2001 AU 1617901 A 30-05-2001

EP 1232150 Al 21-08-2002

W0 0136403 Al 25-05-2001

Form PCT7ISA/210 (paterrtfamily annex) (July 1992)